Modulators of the relaxin receptor 1

ABSTRACT

Disclosed are modulators of the human relaxin receptor 1, for example, of formula (I), wherein A, R 1 , and R 2  are as defined herein, that are useful in treating mammalian relaxin receptor 1 mediated facets of human health, e.g., cardiovascular disease. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the disclosure, and a method for therapeutic intervention in a facet of mammalian health that is mediated by a human relaxin receptor 1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. Divisional application of U.S. applicationSer. No. 14/398,830 filed Nov. 4, 2014, which is a U.S. National Stageapplication of PCT/US2013/032231, filed Mar. 15, 2013, which claimspriority to U.S. Provisional Application No. 61/642,986, filed May 4,2012 all of which are incorporated by reference in their entireties.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under R03 MH085705awarded by the National Institutes of Health. The government has certainrights in this invention.

BACKGROUND

The peptide hormone relaxin was discovered in 1926 as a hormone ofpregnancy, due to its effects to relax pubic ligaments and soften thecervix to facilitate parturition (Hisaw, F. L., Proc. Soc. Exp. Biol.Med. 1926, 23(8), 661-663; Fevold. H. L. et al., J. Am. Chem. Soc. 1930,52(8), 3340-3348). Since then, it has been shown that bloodconcentrations of relaxin rise during the first trimester of pregnancy,promoting cardiovascular and renal adjustments to meet the increasednutritional demands of the growing fetus, and the elevated requirementsfor renal clearance of metabolic wastes (Baylis. C., Am. J. Kidney Dis.1999, 34, 1142-4). Relaxin induces a 20% increase in cardiac output, 30%decrease in systemic vascular resistance, 30% increase in globalarterial compliance, and 45% increase in renal blood flow duringpregnancy (Schrier, R. W. et al., Am. J Kidney Dis. 1987, 9, 284-9).Numerous clinical and nonclinical studies using this hormone have nowrecapitulated these cardiovascular effects in both males and females,demonstrating the pharmacological utility of relaxin in modulatingcardiovascular and renal functions in humans.

The X-ray crystal structure of relaxin at 1.5 Å resolution was reportedfor the physiologically active form of the human hormone in 1991. Thephysiological effects of relaxin are mediated by its interaction with aG protein-coupled receptor (RXFP1) leading to the modulation of severalsignal transduction pathways. Activation of RXFP1 by relaxin induces: 1)up-regulation of the endothelin system which leads to vasodilation; 2)extracellular matrix remodeling through regulation of collagendeposition, cell invasiveness, proliferation, and overall tissuehomeostasis; 3) a moderation of inflammation by reducing levels ofinflammatory cytokines, such as TNF-αt and TGF-β; and 4) angiogenesis byactivating transcription of VEGF. The understanding of the biologicaleffects of RXFP1 activation by relaxin has led to the evaluation ofrelaxin as a pharmacologic agent for the treatment of patients withacute heart failure (AHF), pre-eclampsia, and hypertensive disease. Inaddition, several clinical trials studied the therapeutic role ofrelaxin in treatment of scleroderma, cervical ripening, fibromyalgia,and orthodontics, given its function as anti-inflammatory andextracellular matrix remodeler.

The latest statistics indicate that 1 of every 2.9 deaths in the UnitedStates is due to cardiovascular disease (CVD) (Roger, V. L. et al.,Circulation 2011, 123(4), 459-463). Each year, ˜795,000 peopleexperience a new or recurrent stroke, and 1 in 9 death certificates inthe United States mention heart failure. In addition, 33.5% of US adultsover 20 years of age have hypertension. These statistics clearlyillustrate the limitations of current therapies to address CVD ingeneral and acute heart failure (AHF) in particular. The significantcontribution of vascular dysfunction to the pathophysiology of AHF hasmore recently been recognized. These patients are characterized bypreserved or elevated systolic blood pressure and increased vascularstiffness with less fluid overload. They are more likely to be elderlyand female. Large-scale registry studies suggest that patients withvascular dysfunction causing AHF represent the majority of patients, andthat this may have been underappreciated during previous development ofnew therapies.

Therapeutically, there is a great medical need for better approaches totreat heart failure. Currently, there are two major methodologies: a)surgery and medical devices: coronary bypass surgery, heart valve repairor replacement, implantable cardioverter-defibrillators (ICDs), heartpumps (left ventricular assist devices, or LVADs), or heart transplant;b) medications: angiotensin-converting enzyme (ACE) inhibitors,angiotensin II receptor blockers (ARBs), digoxin (lanoxin), betablockers and aldosterone antagonists. Importantly, none of theseapproaches are able to address the development of scar heart tissueafter severe heart failure, or repair it after damage. In that sense theanti-fibrotic and remodeling properties of relaxin, together with itscapacity to normalize blood pressure, increase blood and renal flow,while it promotes decongestion and vascular compliance, seem to be idealfor treating these conditions. Clinical data agrees with this theory(Teichman S. L. et al, Curr. Heart Failure Rep. 2010, 7, 75-82). Relaxinrelieves systemic and renal vasoconstriction and increases vascularcompliance, including normalization of high blood pressure, reduction ofpulmonary capillary wedge pressure, increase of cardiac output, increaserenal blood flow, natriuresis, and decongestion. In addition, animalpharmacology data indicate that relaxin hormone has anti-inflammatoryand cardiac protection effects, including reduction of myocardialischemia, reduction of reperfusion injury, increase of wound healing,and reduction of ventricular fibrosis.

Recombinant relaxin hormone has produced excellent responses in clinicaltrials for treatment of heart failure and is about to reachcommercialization. However, administration of the peptide is difficultin chronic settings. In view of the foregoing, there is an unmet needfor new small molecule agonists of the RXFP1 receptor.

SUMMARY

The invention provides a compound of the formula (I):

wherein A is 1,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, or—CH₂CH₂—, wherein the 1,2-phenylenyl, 1,2-heteroarylenyl, and1,2-heterocyclyl are optionally substituted with one or moresubstituents independently selected from halo, CF₃, alkyl, alkyloxy,haloalkyl, haloalkoxy, —SR⁷, —SOR⁷, —SO₂R⁷, —SCF₃, and SO₂CF₃,

R₁ is —NHCOR₃, R₄, —NHR₅, or —OR₆,

R₂ is alkyl, cycloalkyl, heteroarylalkyl, orphenyl, which are optionallysubstituted with one or more substituents independently selected fromhalo, CF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkyloxy, trihalo C₁-C₁₀alkyl, perhalo C₁-C₁₀ alkyl, trihalo C₁-C₁₀ alkyloxy, perhalo C₁-C₁₀alkyloxy, aryl, trihaloalkylaryl, perhaloalkylaryl, heterocyclylalkyl,—SR⁷, —SOR⁷, —SO₂R₇, —SCF₃, —NO₂, —CN, and —SO₂CF₃,

R₃ is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, aryl, heteroaryl,arylalkyl, or phenyl, which are optionally substituted with one or moresubstituents independently selected from t halo, CF₃, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy,—SR⁷, —SOR⁷, —SO₂R₇, —SCF₃, —NO₂, —CN, and —SO₂CF₃,

R₄ is phenyl optionally substituted with alkyloxy, haloalkoxy,arylalkyl, or arylalkyloxy,

R₅ is hydrogen, alkyl, alkylaryl, aryl, alkylcycloalkyl, orcycloalkylalkyl which are optionally substituted with one or moresubstituents independently selected from alkyloxy and trifluoromethyl,

R₆ is alkyl optionally substituted with alkylamino, dialkylamino,alkyloxy, and heteroaryl,

and R₇ is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀haloalkyl,C₁-C₁₀haloalkoxy.

The disclosure also provides a pharmaceutical composition comprising acompound or salt of the invention and a pharmaceutically acceptablecarrier.

The disclosure further provides a method for therapeutic intervention ina facet of mammalian health that is mediated by a mammalian relaxinreceptor 1, comprising administering an effective amount of the compoundon the disclosure to a mammal afflicted therewith. In some embodimentsthe mammal is a human and the mammalian relaxin receptor 1 is a humanrelaxin 1 receptor.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1 depicts synthetic schemes for the preparation of compounds inaccordance with embodiments of the disclosure.

FIG. 2 depicts synthetic schemes for the preparation of compounds inaccordance with embodiments of the disclosure.

FIG. 3 depicts synthetic schemes for the preparation of compounds inaccordance with embodiments of the disclosure.

FIG. 4 depicts synthetic schemes for the preparation of compounds inaccordance with embodiments of the disclosure.

FIG. 5 depicts synthetic schemes for the preparation of compounds inaccordance with embodiments of the disclosure.

FIG. 6 depicts synthetic schemes for the preparation of compounds inaccordance with embodiments of the disclosure.

FIG. 7 depicts synthetic schemes for the preparation of compounds inaccordance with embodiments of the disclosure.

FIGS. 1-7 depict synthetic schemes for the preparation of embodiments ofthe disclosure.

FIG. 8A shows the Cell Index in RXFP1 transfected cells in the presenceof Relaxin 10 ng/mL or varied concentrations of compound 178 as apercentage of maximum Relaxin activity, which is assigned a value of100%. FIG. 8B shows the Cell Index, determined as for FIG. 8A, exceptthat varied concentrations of compound 180 are used. FIG. 8C depicts thecell impedence observed for RXFP1 transfected cells in the presence ofRelaxin (10 ng/mL) or compound 178 (750 nM). FIG. 8D depicts the cellimpedence observed for these cells in the presence of Relaxin (10 ng/mL)or compound 180 (750 nM).

FIG. 9 depicts the results of substitution of mouse sequence with humansequence on activation of cAMP in accordance with an embodiment of thedisclosure.

FIG. 10 depicts the activiation of relaxin receptors from human, monkey,pig, and mouse by compound 178.

FIG. 11 depicts the identification of a human RXFP1 region responsiblefor activation by compound 178.

DETAILED DESCRIPTION

The disclosure provides a compound of the formula (I):

wherein A is 1,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, or—CH₂CH₂—, wherein the 1,2-phenylenyl, 1,2-heteroarylenyl, and1,2-heterocyclyl are optionally substituted with one or moresubstituents independently selected from halo, CF₃, alkyl, alkyloxy,haloalkyl, haloalkoxy, —SR₇, —SOR₇, —SO₂R₇, —SCF₃, and SO₂CF₃,

R₁ is —NHCOR₃, R₄, —NHR₅, or —OR₆,

R₂ is alkyl, cycloalkyl, heteroarylalkyl, or phenyl, which areoptionally substituted with one or more substituents independentlyselected from halo, CF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkyloxy,C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, aryl, haloalkylaryl,heterocyclylalkyl, —SR₇, —SOR₇, —SO₂R₇, —SCF₃, —NO₂, —CN, and —SO₂CF₃,

R₃ is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, aryl, heteroaryl,arylalkyl, or phenyl, each of which are optionally substituted with oneor more substituents independently selected from halo, CF₃, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl,C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, —SO₂R₇, —SCF₃, —NO₂, —CN, and —SO₂CF₃,

R₄ is phenyl optionally substituted with alkyloxy, haloalkyloxy,arylalkyl, or arylalkyloxy,

R₅ is hydrogen, alkyl, alkylaryl, aryl, alkylcycloalkyl, orcycloalkylalkyl which are optionally substituted with one or moresubstituents independently selected from alkyloxy and trifluoromethyl,

R₆ is alkyl optionally substituted with alkylamino, dialkylamino,alkyloxy, and heteroaryl,

and R₇ is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀haloalkyl orC₁-C₁₀haloalkoxy,

with the provisos that:

(i) when R₃ is methyl, chloromethyl, or dichloromethyl, and A is1,2-phenylenyl, then R₂ is not methyl, phenyl, 2-methylphenyl,2-methoxyphenyl, or 4-methoxyphenyl; and

(ii) when R₃ is phenyl, and A is 1,2-phenylenyl, then R₂ is nothalophenyl, methoxyphenyl, 2,6-dimethylphenyl, or 2,4,6-trimethylphenyl;and

(iii) when R₃ is phenyl substituted with alkyl, and A is 1,2-phenylenyl,then R₂ is not methoxyphenyl;

or a pharmaceutically acceptable salt thereof.

In accordance with certain embodiments, R₂ is phenyl substituted with asubstituent selected from —SO₂CF₃, —SCF₃, and —CF3.

In accordance with certain embodiments, A is 1,2-phenylene optionallysubstituted with one or more substituents selected from hydrogen, halo,—CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, —SR₇, —SOR₇, —SO₂R₇,—SCF₃, and —SO₂CF₃.

In accordance with certain embodiments, R1 is —NHCOR3, wherein R3 isphenyl substituted with a substituent selected from —CF₃, C₁-C₁₀alkyl,C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, alkyloxyalkyloxy,dimethylaminoalkyloxy, —SR₇, —SOR₇, —SO₂R₇, —SCF₃, and —SO₂CF₃.

In accordance with certain preferred embodiments, R₃ is2-(C₁-C₁₀)alkyloxyphenyl.

In accordance with certain preferred embodiments, R2 is phenylsubstituted with a substituent selected from —CF₃, C₁-C₁₀ alkyl, C₁-C₁₀alkyloxy, C₁-C₁₀haloalkyl, C1-C10haloalkoxy, —SR₇, —SOR₇, —SO₂R₇, —SCF₃,and —SO₂CF₃.

In certain preferred embodiments, the compound is selected from thegroup consisting of:

In accordance with certain embodiments, R₁ is R₄, wherein R₄ is2-(C₁-C₁₀)alkyloxyphenyl or 2-(C₁-C₁₀) haloalkyloxyphenyl.

In accordance with certain preferred embodiments, R₁ is —NHR₅, whereinR₅ is aryl optionally substituted with one or more substituents selectedfrom alkyloxy and trifluoromethyl.

In accordance with certain embodiments, R₁ is —OR₆, wherein R₆ is alkyloptionally substituted with alkylamino, dialkylamino, alkyloxy, andheteroaryl.

In accordance with certain embodiments, A is 1,2-heteroarylenyloptionally substituted with one or more substitutents independentlyselected from halo, —CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, —SR₇,—SOR₇, —SO₂R₇, —SCF₃, and —SO₂CF₃.

In accordance with certain preferred embodiments, A is selected from

In accordance with certain preferred embodiments, R₁ is —NHCOR₃, whereinR₃ is phenyl substituted with a substituent selected from the groupconsisting of —CF₃, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl,C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, —SO₂R₇, —SCF₃, and —SO₂CF₃.

In accordance with certain preferred embodiments, R₃ is2-(C₁-C₁₀)alkyloxyphenyl or 2-(C₁-C₁₀)haloalkyloxyphenyl.

In certain preferred embodiments, wherein the compound is selected fromthe group consisting of:

In accordance with certain embodiments, A is —CH₂CH₂—.

In accordance with certain embodiments, wherein R₁ is —NHCOR₃, whereinR₃ is phenyl substituted with a substituent independently selected from—CF₃, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy,—SR₇, —SOR₇, —SO₂R₇, —SCF₃, and —SO₂CF₃.

In accordance with certain embodiments, R₃ is 2-(C₁-C₁₀)alkyloxyphenylor 2-(C₁-C₁₀)haloalkyloxyphenyl.

In accordance with a particular embodiment, the compound is:

The disclosure provides compounds and pharmaceutically acceptablethereof, having the formula

is a 3- to 8-membered carbocyclic ring or a 3- to 8-memberedheterocyclic ring containing 1 to 3 heteroatoms independently chosenfrom N, O, and S, each of which A ring is optionally fused to a 3- to8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ringcontaining 1 to 3 heteroatoms independently chosen from N, O, and S, toform a bicylic ring system; and the A ring and 3- to 8-memberedcarbocyclic or heterocyclic ring to which A is optionally fused are eachsubstituted with R₁₀;

m, n, o, and p are integers independently chosen from 0, 1, and 2 andeach of

is unsubstituted or substituted with one or more substituentsindependently chosen from halogen, hydroxyl, C₁-C₂alkyl, andC₁-C₂alkoxy;

X and Y are independently chosen from O and S;

R₈ and R₉ are independently chosen from hydrogen and C₁-C₄alkyl;

R₁₀, R₂₁, and R₃₁ are each 0 to 3 substitutents independently chosenfrom hydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy,mono- and di-(C₁-C₂alkyl)amino-, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R₂₀ is NO₂, CN, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, or—SO₂R₇, where R₇ is C₁-C₁₀carbyhdryl or C₁-C₁₀haloalkyl;

R₃₀ is hydrogen or R₃₀ is C₁-C₈carbhydryloxy or C₁-C₈carbhydrylthio-each or which is substituted with 0 to 3 substituents independentlychosen from hydroxyl, halogen, nitro, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In another embodiment the disclosure includes a compound or salt ofFormula X where

is a phenyl or 5- or 6-membered heteroaryl group containing 1 to 3heteroatoms independently chosen from N, O, and S, each of which A ringis optionally fused to 5- or 6-membered carbocyclic or heterocyclic ringto form a bicylic ring system; and the A ring and 5- or 6-memberedcarbocyclic or heterocyclic ring to which A is optionally fused are eachsubstituted with R₁₀.

The disclosure includes compounds or salts for Formula X where

is a group of formula

each of which is substituted with R₁₀.

The disclosure includes compounds or salts for Formula X, wherein m, n,o, and p are all 0 and X and Y are both O.

The disclosure includes compounds or pharmaceutically salts for FormulaXI

where:

R₁₀, R₂₁, and R₃₁ are each 0 to 3 substitutents independently chosenfrom hydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy,mono- and di-(C₁-C₂alkyl)amino-, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R₂₀ is NO₂, CN, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, or—SO₂R₇, where R₇ is C₁-C₁₀alkyl or C₁-C₁₀haloalkyl;

R₃₀ is hydrogen or R₃₀ is C₁-C₈alkoxy or C₁-C₈alkylthio- each or whichis substituted with 0 to 3 substituents independently chosen fromhydroxyl, halogen, nitro, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The disclosure includes compounds and salts of Formula XI, wherein R₂₀is C₁-C₆haloalkyl, —S(C₁-C₆haloalkyl), or —SO₂(C₁-C₆haloalkyl).

The disclosure includes compounds and salts of Formula XI, wherein R₁₀,R₂₁, and R₃₁ are each 0 substituents.

The disclosure includes compounds and salts of Formula XI, wherein R₁₀,R₂₁, and R₃₁ are each 0 substituents; R₂₀ is CF₃, SCF₃, or SO₂CF₃, andR₃₀ is C₂-C₆alkoxy or C₂-C₆alkylthio-, each of which is substituted with0 to 2 substituents independently chosen from halogen and —CF₃.

The disclosure includes compounds and salts of Formula XI, wherein R₂₀is SO₂CF₃.

The disclosure includes compounds and salts of Formula XII

where:

R₁₀ and R₃₁ are each 0 to 3 substitutents independently chosen fromhydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono-and di-(C₁-C₂alkyl)amino-, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; and

R₂ is (phenyl)C₀-C₂alkyl- or (5- or 6-membered heteroaryl)C₀-C₂alkyl,each of which is substituted with 0 or 1 or more substituentsindependently chosen from hydroxyl, halogen, nitro, cyano, amino,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, 5-and 6-membered heterocycloalkyl, thienyl, phenyl, phenyl substitutedwith CF₃, mono- and di-C₁-C₆alkylamino, C₁-C₆alkylthio,C₁-C₆alkylsulfonyl C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,—SR₇, —SOR₇, and —SO₂R₇, where R₇ is C₁-C₁₀carbhydryl orC₁-C₁₀haloalkyl; or

R₂ is dihydroindenyl, benzo[d][1,3]dioxolyl, or indolyl, each of whichis substituted with 0 to 3 substitutents independently chosen fromhydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono-or di-(C₁-C₂alkyl)amino-, C₁-C₂haloalkyl, and C₁-C₂halo alkoxy.

The disclosure includes compounds and salts of Formula XII, wherein R₁₀and R₃₁ are both 0 substituents.

The disclosure includes compounds and salts of Formula XII, wherein

R₂ is phenyl substituted with one or two substituents independentlychosen from hydroxyl, halogen, nitro, SCF₃, SO₂CF₃, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, 5- and 6-membered heterocycloalkyl, thienyl,phenyl, phenyl substituted with CF₃, mono- and di-C₁-C₆alkylamino,C₁-C₆alkylthio, C₁-C₆alkylsulfonyl C₁-C₄alkoxy, C₁-C₂haloalkyl, andC₁-C₂halo alkoxy.

The disclosure includes compounds and salts of Formula XII, wherein R₂is phenyl substituted in the meta position with CF₃, SCF₃, or SO₂CF₃.

The disclosure includes compounds and salts of Formula XII, wherein

R₂ is 2,3-dihydro-1H-indenyl, benzo[d][1,3]dioxolyl, or indolyl, each ofwhich is unsubstituted.

The disclosure includes compounds and pharmaceutically acceptable saltsof Formula XIII

where:

R₁₀ and R₂₁ are each 0 to 3 substitutents independently chosen fromhydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono-and di-(C₁-C₂alkyl)amino-, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R₂₀ is NO₂, CN, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, or—SO₂R₇, where R₇ is C₁-C₁₀carbhydryl or C₁-C₁₀haloalkyl; and

R₃ is cyclohexyl; or

R₃ is phenyl substituted with one or more substituents independentlychosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, SO₂CF₃,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl mono- anddi-C₁-C₆alkylamino, C₁-C₆alkylthio, C₁-C₆alkylsulfonyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The disclosure includes compounds and salts of Formula XIII, wherein R₁₀and R₂₁ are both 0 substituents and R₃ is phenyl substituted with onemeta-position substituent.

The disclosure includes compounds and salts of Formula XIII, wherein R₁₀and R₂₁ are both 0 substituents and R₂₀ is CF₃, SCF₃, or SO₂CF₃.

The disclosure includes compounds and salts of Formula XIII, wherein R₂₀is CF₃; and

R₃ is phenyl substituted with one or more substituents independentlychosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, SO₂CF₃,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl mono- anddi-C₁-C₆alkylamino, C₁-C₆alkylthio, C₁-C₆alkylsulfonyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The disclosure includes compounds and salts of Formula XIII, wherein R₂₀is SO₂CF₃; and

R₃ is phenyl substituted with one or more substituents independentlychosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, SO₂CF₃,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl mono- anddi-C₁-C₆alkylamino, C₁-C₆alkylthio, C₁-C₆alkylsulfonyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The disclosure includes compounds and salts of Formula X, wherein

is group of formula

each of which is substituted with R₁₀.

Additionally in certain embodiments where the A-ring is a thienyl orpyridyl R₁₀, R₂₁, and R₃₁ are each 0 substituents.

The disclosure also includes compounds and salts where the A ring is athienyl or pyridyl, wherein each of m, n, o, and p are 0 and X and Y areboth O.

The disclosure also includes compounds and salts where the A ring is athienyl or pyridyl R₂₀ is NO₂, CN, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy,—SR₇, —SOR₇, or —SO₂R₇, where R₇ is C₁-C₁₀alkyl or C₁-C₁₀haloalkyl; and

R₃₀ is hydrogen or R₃₀ is C₁-C₈alkoxy or C₁-C₈alkylthio- each or whichis substituted with 0 to 3 substituents independently chosen fromhydroxyl, halogen, nitro, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The disclosure also includes compounds and salts where the A ring is athienyl or pyridyl, wherein R₂₀ is C₁-C₆haloalkyl, —S(C₁-C₆haloalkyl),or —SO₂(C₁-C₆haloalkyl).

The disclosure also includes compounds and salts where the A ring is athienyl or pyridyl, wherein R₁₀, R₂₁, and R₃₁ are each 0 substituents;R₂₀ is CF₃, SCF₃, or SO₂CF₃, and R₃₀ is C₂-C₆alkoxy or C₂-C₆alkylthio-,each of which is substituted with 0 to 2 substituents independentlychosen from halogen and —CF₃.

The disclosure also includes compounds and salts where the A ring is athienyl or pyridyl, wherein R₂₀ is SO₂CF₃.

The disclosure further includes compounds and salts of Formula XIV

m, n, o, and p are integers independently chosen from 0, 1, and 2 andeach of

is unsubstituted or substituted with one or more substituentsindependently chosen from halogen, hydroxyl, C₁-C₂alkyl, andC₁-C₂alkoxy;

X and Y are independently chosen from O and S;

R₈ and R₉ are independently chosen from hydrogen and C₁-C₄alkyl;

R₁₀, R₂₁, and R₃₁ are each 0 to 3 substitutents independently chosenfrom hydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy,mono- and di-(C₁-C₂alkyl)amino-, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R₂₀ is NO₂, CN, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, or—SO₂R₇, where R₇ is C₁-C₁₀carbyhdryl or C₁-C₁₀haloalkyl;

R₃₀ is hydrogen or R₃₀ is C₁-C₈carbhydryloxy or C₁-C₈carbhydrylthio-each or which is substituted with 0 to 3 substituents independentlychosen from hydroxyl, halogen, nitro, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The disclosure includes compounds and salts of Formula XIV, wherein m,n, o, and p are all 0 and X and Y are both O.

The disclosure includes compounds and salts of Formula XV

where:

R₁₀, R₂₁, and R₃₁ are each 0 to 3 substitutents independently chosenfrom hydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy,mono- and di-(C₁-C₂alkyl)amino-, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R₂₀ is NO₂, CN, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, or—SO₂R₇, where R₇ is C₁-C₁₀alkyl or C₁-C₁₀haloalkyl;

R₃₀ is hydrogen or R₃₀ is C₁-C₈alkoxy or C₁-C₈alkylthio- each or whichis substituted with 0 to 3 substituents independently chosen fromhydroxyl, halogen, nitro, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The disclosure includes compounds and salts of Formula XVI

where:

R₁₀, R₂₁, and R₃₁ are each 0 to 3 substitutents independently chosenfrom hydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy,mono- and di-(C₁-C₂alkyl)amino-, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R₂₀ is NO₂, CN, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, or—SO₂R₇, where R₇ is C₁-C₁₀alkyl or C₁-C₁₀haloalkyl;

R₃₀ is hydrogen or R₃₀ is C₁-C₈alkoxy or C₁-C₈alkylthio- each or whichis substituted with 0 to 3 substituents independently chosen fromhydroxyl, halogen, nitro, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The disclosure includes compounds of Formula XV and XVI, wherein R₂₀ isC₁-C₆haloalkyl, —S(C₁-C₆haloalkyl), or —SO₂(C₁-C₆haloalkyl).

The disclosure includes compounds of Formula XV and XVI, wherein R₂₁,and R₃₁ are both 0 substituents.

The disclosure includes compounds of Formula XV and XVI, wherein R₂₁ andR₃₁ are both 0 substituents; R₂₀ is CF₃, SCF₃, or SO₂CF₃, and R₃₀ isC₂-C₆alkoxy or C₂-C₆alkylthio-, each of which is substituted with 0 to 2substituents independently chosen from halogen and —CF₃.

The disclosure includes compounds of Formula XV and XVI, wherein R₂₀ isSO₂CF₃.

Any of the variable definitions set forth herein (e.g. R₁₀, R₂₀, R₂₁,R₃₀, R₃₁, R₈, R₉, X, Y, m, n, o, and p) may be combined so long as astable compound results, and all such combinations which result in astable compound are included as compounds within the scope of thedisclosure.

Any of the genuses, subgenuses, and compounds in the scope of thedisclosure, including compounds and salts of Formula X to Formula XVI,can be used for treating any of the conditions, disorders, diseases, orother facets of mammalian health listed in this application.

Any of the genuses, subgenuses, and compounds of the disclosure,including compounds and salts of Formula X to XI can be used for themanufacture of a medicament for any of the conditions, disorders,diseases, or other facets of mammalian health listed in thisapplication.

Referring now to terminology used generically herein, the term “alkyl”means a straight-chain or branched alkyl substituent containing from,for example, 1 to about 10 carbon atoms, preferably from 1 to about 4carbon atoms, more preferably from 1 to 2 carbon atoms. Examples of suchsubstituents include methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, and the like.

The term “alkenyl,” as used herein, means a linear or branched alkenylsubstituent containing at least one carbon-carbon double bond and from,for example, linear alkenyl of about 2 to about 10 carbon atoms(branched alkenyls are about 3 to about 6 carbons atoms), preferablyfrom about 2 to about 5 carbon atoms (branched alkenyls are preferablyfrom about 3 to about 5 carbon atoms), more preferably linear alkenyl ofabout 3 to about 4 carbon atoms. Examples of such substituents includevinyl, propenyl, isopropenyl, n-butenyl, sec-butenyl, isobutenyl,tert-butenyl, pentenyl, isopentenyl, hexenyl, and the like.

The term “alkynyl,” as used herein, means a linear or branched alkynylsubstituent containing at least one carbon-carbon triple bond and from,for example, linear alkynyl of 2 to about 10 carbon atoms (branchedalkynyls are about 3 to about 6 carbons atoms), preferably from 2 toabout 5 carbon atoms (branched alkynyls are preferably from about 3 toabout 5 carbon atoms), more preferably linear alkynyl of about 3 toabout 4 carbon atoms. Examples of such substituents include ethynyl,propynyl, isopropynyl, n-butynyl, sec-butynyl, isobutynyl, tert-butynyl,pentynyl, isopentynyl, hexynyl, and the like.

“Carbhydryl” is a hydrocarbon group that is straight, branched or cyclic(including (cycloalkyl)alkyl) and contains any combination of single,double, and triple covalent bonds. For example a carbhydryl group may bean alkyl, alkenyl, or alkynyl group. When the term carbhydryl is used inconjuction with “oxy” carbhydryl is a group as defined covalently boundto the group it substitutes through an oxygen, —O—, bridge. Similarly,carbhydrylthio is a carbhydryl group as defined covalently bound to thegroup it substitutes through a sulfur, —S—, bridge.

The term “cycloalkyl,” as used herein, means a cyclic alkyl substituentcontaining from, for example, about 3 to about 8 carbon atoms,preferably from about 4 to about 7 carbon atoms, and more preferablyfrom about 4 to about 6 carbon atoms. Examples of such substituentsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like. The cyclic alkyl groups may be unsubstitutedor further substituted with alkyl groups such as methyl groups, ethylgroups, and the like.

The term “bicycloalkyl”, as used herein, means a bicyclic alkylsubstituent containing from, for example, about 4 to about 12 carbonatoms, preferably from about 4 to about 7 carbon atoms, and morepreferably from about 6 to about 10 carbon atoms. Examples of suchsubstituents include bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl,bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, and the like. The bicyclicalkyl groups may be unsubstituted or further substituted with alkylgroups such as methyl groups, ethyl groups, and the like.

The term tricycloalkyl”, as used herein, means a tricyclic alkylsubstituent containing from, for example, about 6 to about 18 carbonatoms, preferably from about 8 to about 16 carbon atoms. Examples ofsuch substituents include adamantyl and the like. The tricyclic alkylgroups may be unsubstituted or further substituted with alkyl groupssuch as methyl groups, ethyl groups, and the like.

“Haloalkyl” indicates both branched and straight-chain alkyl groupshaving the specified number of carbon atoms, substituted with 1 or morehalogen atoms, up to the maximum allowable number of halogen atoms.Examples of haloalkyl include, but are not limited to, trifluoromethyl,difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined herein attachedthrough an oxygen bridge (oxygen of an alcohol radical). The term“heterocyclyl,” or “heterocyclic” as used herein, refers to a monocyclicor bicyclic 3- to 8-membered ring system containing one or moreheteroatoms selected from O, N, S, and combinations thereof. Theheterocyclyl group can be any suitable heterocyclyl group and can be analiphatic heterocyclyl group, an aromatic heterocyclyl group, or acombination thereof. The heterocyclyl group can be a monocyclicheterocyclyl group or a bicyclic heterocyclyl group. Suitable bicyclicheterocyclyl groups include monocylic heterocyclyl rings fused to aC₆-C₁₀ aryl ring. When the heterocyclyl group is a bicyclic heterocyclylgroup, both ring systems can be aliphatic or aromatic, or one ringsystem can be aromatic and the other ring system can be aliphatic as in,for example, dihydrobenzofuran. Preferably, the heterocyclyl group is anaromatic heterocyclyl group. Non-limiting examples of suitableheterocyclyl groups include furanyl, thiopheneyl, pyrrolyl, pyrazolyl,imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-2-yl,5-methyl-1,3,4-oxadiazole, 3-methyl-1,2,4-oxadiazole, pyridinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiopheneyl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolinyl,benzothiazolinyl, and quinazolinyl. The heterocyclyl group is optionallysubstituted with 1, 2, 3, 4, or 5 substituents as recited herein such aswith alkyl groups such as methyl groups, ethyl groups, and the like, orwith aryl groups such as phenyl groups, naphthyl groups and the like,wherein the aryl groups can be further substituted with, for examplehalo, dihaloalkyl, trihaloalkyl, nitro, hydroxy, alkoxy, aryloxy, amino,substituted amino, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl,aryloxycarbonyl, thio, alkylthio, arylthio, and the like, wherein theoptional substituent can be present at any open position on theheterocyclyl group.

The term “heteroaryl,” as used herein, refers to a monocyclic orbicyclic 5- or 6-membered ring system containing one or more heteroatomsselected from O, N, S, and combinations thereof. The heteroaryl groupcan be any suitable heteroaryl. The heteroaryl group can be a monocyclicheteroaryl group or a bicyclic heteroaryl group. Suitable bicyclicheteroaryl groups include monocylic heteroaryl rings fused to a C₆-C₁₀aryl ring. When the heteroaryl group is a bicyclic heteroaryl group,both ring systems are preferably aryl. Non-limiting examples of suitableheteroaryl groups include furanyl, thiopheneyl, pyrrolyl, pyrazolyl,imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzoxazolinyl, benzothiazolinyl, and quinazolinyl. Theheteroaryl group is optionally substituted with 1, 2, 3, 4, or 5substituents as recited herein, wherein the optional substituent can bepresent at any open position on the heteroaryl group.

The terms “heteroarylalkyl” and “heterocyclylalkyl,” as used herein,refers to a heteroaryl or heterocyclyl group as defined herein having analkyl linker group attached thereto, wherein the heteroarylalkyl andheterocyclylalkyl groups are attached to the rest of the molecule viathe alkyl linker group.

The terms “1,2-phenylenyl” and “1,2-heteroarylenyl,” as used herein,refer to a phenyl group or a heteroaryl group having attached to thering two groups positioned at adjacent positions on the phenyl orheteroaryl group, i.e., forming an ortho substitution on the phenyl orheteroaryl group.

The term “arylalkyl,” as used herein, refers to an alkyl group linked toa C₆-C₁₀ aryl ring and further linked to a molecule via the alkyl group.The term “alkylaryl,” as used herein, refers to a C₆-C₁₀ aryl ringlinked to an alkyl group and further linked to a molecule via the arylgroup.

The term “alkylcarbonyl,” as used herein, refers to an alkyl grouplinked to a carbonyl group and further linked to a molecule via thecarbonyl group, e.g., alkyl-C(═O)—. The term “alkoxycarbonyl,” as usedherein, refers to an alkoxy group linked to a carbonyl group and furtherlinked to a molecule via the carbonyl group, e.g., alkyl-O—C(═O)—.

Whenever a range of the number of atoms in a structure is indicated(e.g., a C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₂-C₁₂, C₂-C₈, C₂-C₆, C₂-C₄alkyl, alkenyl, alkynyl, etc.), it is specifically contemplated that anysub-range or individual number of carbon atoms falling within theindicated range also can be used. Thus, for instance, the recitation ofa range of 1-8 carbon atoms (e.g., C₁-C₈), 1-6 carbon atoms (e.g.,C₁-C₆), 1-4 carbon atoms (e.g., C₁-C₄), 1-3 carbon atoms (e.g., C₁-C₃),or 2-8 carbon atoms (e.g., C₂-C₈) as used with respect to any chemicalgroup (e.g., alkyl, alkylamino, etc.) referenced herein encompasses andspecifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and/or 12carbon atoms, as appropriate, as well as any sub-range thereof (e.g.,1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms,1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms,1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms, 2-3 carbonatoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbonatoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms,4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms,4-10 carbon atoms, 4-11 carbon atoms, and/or 4-12 carbon atoms, etc., asappropriate). Similarly, the recitation of a range of 6-10 carbon atoms(e.g., C₆-C₁₀) as used with respect to any chemical group (e.g., aryl)referenced herein encompasses and specifically describes 6, 7, 8, 9,and/or 10 carbon atoms, as appropriate, as well as any sub-range thereof(e.g., 6-10 carbon atoms, 6-9 carbon atoms, 6-8 carbon atoms, 6-7 carbonatoms, 7-10 carbon atoms, 7-9 carbon atoms, 7-8 carbon atoms, 8-10carbon atoms, and/or 8-9 carbon atoms, etc., as appropriate).

The term “halo” or “halogen,” as used herein, means a substituentselected from Group VIIA, such as, for example, fluorine, bromine,chlorine, and iodine.

The term “aryl” refers to an unsubstituted or substituted aromaticcarbocyclic substituent, as commonly understood in the art, and the term“C₆-C₁₀ aryl” includes phenyl and naphthyl. It is understood that theterm aryl applies to cyclic substituents that are planar and comprise4n+2π electrons, according to Hückel's Rule. The term “carbocyclic’refers to an aliphatic or aromatic ring containing only carbon ringatoms.

The phrase “pharmaceutically acceptable salt” is intended to includenontoxic salts synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two.Generally, nonaqueous media such as ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 18th ed., Mack PublishingCompany, Easton, Pa., 1990, p. 1445, and Journal of PharmaceuticalScience, 66, 2-19 (1977).

Suitable bases include inorganic bases such as alkali and alkaline earthmetal bases, e.g., those containing metallic cations such as sodium,potassium, magnesium, calcium and the like. Non-limiting examples ofsuitable bases include sodium hydroxide, potassium hydroxide, sodiumcarbonate, and potassium carbonate. Suitable acids include inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid, maleic acid, tartaric acid, fattyacids, long chain fatty acids, and the like. Preferred pharmaceuticallyacceptable salts of inventive compounds having an acidic moiety includesodium and potassium salts. Preferred pharmaceutically acceptable saltsof inventive compounds having a basic moiety (e.g., a dimethylaminoalkylgroup) include hydrochloride and hydrobromide salts. The compounds ofthe present disclosure containing an acidic or basic moiety are usefulin the form of the free base or acid or in the form of apharmaceutically acceptable salt thereof.

It should be recognized that the particular counterion forming a part ofany salt of this disclosure is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole.

It is further understood that the above compounds and salts may formsolvates, or exist in a substantially uncomplexed form, such as theanhydrous form. As used herein, the term “solvate” refers to a molecularcomplex wherein the solvent molecule, such as the crystallizing solvent,is incorporated into the crystal lattice. When the solvent incorporatedin the solvate is water, the molecular complex is called a hydrate.Pharmaceutically acceptable solvates include hydrates, alcoholates suchas methanolates and ethanolates, acetonitrilates and the like. Thesecompounds can also exist in polymorphic forms.

The compounds of the disclosure can be synthesized using any suitablesynthetic route. Referring to FIG. 1, methyl 2-aminobenzoate 500 can bereacted with an acid chloride in the presence of a base such astriethylamine in a solvent such as dichloromethane to provide amide 501.Amide 501 can be reacted with an amine in the presence of a catalystsuch as trimethylaluminum in a solvent such as toluene to providebis-amide 502. Compound 503 can be reacted with a boronic acid in thepresence of a catalyst such as Pd(PPh₃)₄, a base such as sodiumcarbonate, in a solvent such as dimethylformamide under microwaveirradiation to give the coupled product 504. Arylthiol compound 505 canbe oxidized with an agent such as m-chloroperoxybenzoic acid in asolvent such as dichloromethane to give sulfone 506. The cyano compound507 can be reacted with ammonium chloride in the presence of a catalystsuch as trimethylaluminum in a solvent such as toluene to give amidine508. Reaction of amidine 508 with an azide such as sodium azide in thepresence of a catalyst such as zinc bromide in a solvent such as watergives tetrazole 510.

Referring to FIG. 2, carboxylic acid 511 can be reacted with an aminesuch as 1,3-trilfuoromethylaniline in the presence of a coupling agentsuch as EDC and a basic catalyst such as dimethylaminopyridine in asolvent such as dichloromethane, followed by deprotection with an agentsuch as trifluoroacetic acid in a solvent such as dichloromethane togive free amine 513. Reaction of amine 513 with a carboxylic acid in thepresence of coupling agents such as EDC or HATU in the presence of abasic catalyst such as dimethylaminopyridine in a solvent such asdimethylformamide gives amide 514. Alternatively, reaction of amine 513with an acid chloride or an acid bromide in the presence of a base suchas triethylamine in a solvent such as dichloromethane provides amide514.

Referring to FIG. 3, reaction of aryl iodide 515 with an alcohol in thepresence of a catalyst such as 1,10-phenanthroline and a base such ascesium carbonate in a solvent such as toluene gives aryl ether 516.Reaction of 2-bromobenzoyl chloride or 2-iodobenzoyl chloride 517 with3-trifluoromethylaniline in the presence of a base such as triethylaminein a solvent such as dichloromethane provides amide 518. Amide 518reacts with a boronic acid in the presence of a catalyst such asPd(PPh₃)₄, a base such as sodium carbonate, in a solvent such asdimethylformamide under microwave irradiation gives alkylated/arylatedcompound 519. Reaction of compound 518 with a primary amine in thepresence of a catalyst such as cuprous chloride in a solvent such asdimethylformanide provides arylamine 520. Reaction of 518 with analcohol in the presence of catalysts such as copper (I) iodide and1,10-phenanthroline in the presence of a base such as cesium carbonatein a solvent such as toluene gives aryl ether 521.

Referring to FIG. 4, reaction of amide 522 with an alkylating agent suchas iodomethane in the presence of a base such as NaH in a solvent suchas dimethylformamide gives N-methylamide 523. Compound 523 reacts withan arylamine such as compound 524 in the presence of a catalyst such astrimethylaluminum in a solvent such as toluene to give bis-amide 525.Oxidation of alcohol 526 with an oxidant such as Dess-Martin periodinanein a solvent such as dichloromethane gives aldehyde 527. Reductiveamination of aldehyde 527 with an amine such as 528 in the presence of acatalyst such as Ti(OiPr)₄ and a reductant such as sodium borohydridegives amine 529. Deprotection of Boc compound 529 with an agent such astrifluoroacetic acid in a solvent such as dichloromethane givesarylamine 530. Coupling of arylamine 530 with an acyl chloride such as531 in the presence of a base such as triethylamine in a solvent such asdichloromethane gives amine-amide 532. Sulfonamides can be prepared byreaction of methyl 2-aminobenzoate 533 with sulfonyl chloride 534 in thepresence of a base such as triethylamine in a solvent such asdichloromethane to give sulfonamide 535. Reaction of 535 with3-trifluoromethylsulfonylaniline in the presence of a catalyst such astrimethylaluminum in a solvent such as toluene gives compound 536.

Referring to FIG. 5, aniline derivative 537 can be reacted with an acylchloride in the presence of a base such as triethylamine in a solventsuch as dichloromethane to provide amide 538. Reaction of 538 with3-trifluoromethylaniline in the presence of a catalyst such astrimethylaluminum in a solvent such as toluene gives bis-amide 539. Thesame chemistry can be performed substituting heterocyclic/heteroarylanalogs of compound 537.

Referring to FIG. 6, cyclization of amino amide 543 in a solvent such asacetic acid at room temperature provides benzimidazole 544. Cyclizationat 70° C. gives a mixture of isomeric tetracyclic compounds 545 and 546.Reaction of bis-amine compound 547 with an acid chloride such as2-ethoxybenzoyl chloride in the presence of a base such as triethylaminein a solvent such as dichloromethane gives amino amide 548. Cyclizationof 548 in a solvent such as acetic acid gives benzimidazole 549.Amidation of 549 with 3-trifluoromethylsulfonylaniline in the presenceof a catalyst such as trimethylaluminum in a solvent such as toluenegives compound 550. Reaction of amine 551 with 3-iodotrifluorobenzene inthe presence of a catalyst such as 1,2-methylaminocyclohexane in thepresence of a catalyst such as copper (I) iodide and a base such aspotassium carbonate in a solvent such as toluene gives the coupledproduct 553. Reaction of 553 with 2-ethoxybenzoyl chloride in thepresence of a base such as triethylamine in a solvent such asdichloromethane gives amide 554.

Referring to FIG. 7, reaction of aryl iodide 555 with an alcohol or athiol in the presence of catalysst such as copper (I) iodide chlorideand 1,10-phenanthroline in the presence of base such as cesium carbonatein a solvent such as toluene gives aryl ether 556.

The present disclosure is further directed to a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one compound or salt described herein.

It is preferred that the pharmaceutically acceptable carrier be one thatis chemically inert to the active compounds and one that has nodetrimental side effects or toxicity under the conditions of use.

The choice of carrier will be determined in part by the particularcompound of the present disclosure chosen, as well as by the particularmethod used to administer the composition. Accordingly, there is a widevariety of suitable formulations of the pharmaceutical composition ofthe present disclosure. The following formulations for oral, aerosol,nasal, pulmonary, parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, intrathecal, intratumoral, topical, rectal, and vaginaladministration are merely exemplary and are in no way limiting.

The pharmaceutical composition can be administered parenterally, e.g.,intravenously, subcutaneously, intradermally, or intramuscularly. Thus,the disclosure provides compositions for parenteral administration thatcomprise a solution or suspension of the inventive compound or saltdissolved or suspended in an acceptable carrier suitable for parenteraladministration, including aqueous and non-aqueous isotonic sterileinjection solutions.

Overall, the requirements for effective pharmaceutical carriers forparenteral compositions are well known to those of ordinary skill in theart. See, e.g., Banker and Chalmers, eds., Pharmaceutics and PharmacyPractice, J. B. Lippincott Company, Philadelphia, pp. 238-250 (1982),and Toissel, ASHP Handbook on Injectable Drugs, 4th ed., pp. 622-630(1986). Such solutions can contain anti-oxidants, buffers,bacteriostats, and solutes that render the formulation isotonic with theblood of the intended recipient, and aqueous and non-aqueous sterilesuspensions that can include suspending agents, solubilizers, thickeningagents, stabilizers, and preservatives. The compound or salt of thepresent disclosure may be administered in a physiologically acceptablediluent in a pharmaceutical carrier, such as a sterile liquid or mixtureof liquids, including water, saline, aqueous dextrose and related sugarsolutions, an alcohol, such as ethanol, isopropanol, or hexadecylalcohol, glycols, such as propylene glycol or polyethylene glycol,dimethylsulfoxide, glycerol ketals, such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such aspoly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester orglyceride, or an acetylated fatty acid glyceride with or without theaddition of a pharmaceutically acceptable surfactant, such as a soap ora detergent, suspending agent, such as pectin, carbomers,methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agents and other pharmaceuticaladjuvants.

Oils useful in parenteral formulations include petroleum, animal,vegetable, or synthetic oils. Specific examples of oils useful in suchformulations include peanut, soybean, sesame, cottonseed, corn, olive,petrolatum, and mineral. Suitable fatty acids for use in parenteralformulations include oleic acid, stearic acid, and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acidesters.

Suitable soaps for use in parenteral formulations include fatty alkalimetal, ammonium, and triethanolamine salts, and suitable detergentsinclude (a) cationic detergents such as, for example, dimethyl dialkylammonium halides, and alkyl pyridinium halides, (b) anionic detergentssuch as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin,ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionicdetergents such as, for example, fatty amine oxides, fatty acidalkanolamides, and polyoxyethylenepolypropylene copolymers, (d)amphoteric detergents such as, for example, alkyl-beta-aminopropionates,and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixturesthereof.

The parenteral formulations can contain preservatives and buffers. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain one or more nonionic surfactants having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulations will typically range fromabout 5 to about 15% by weight. Suitable surfactants includepolyethylene sorbitan fatty acid esters, such as sorbitan monooleate andthe high molecular weight adducts of ethylene oxide with a hydrophobicbase, formed by the condensation of propylene oxide with propyleneglycol. The parenteral formulations can be presented in unit-dose ormulti-dose sealed containers, such as ampules and vials, and can bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid excipient, for example, water, forinjections, immediately prior to use. Extemporaneous injection solutionsand suspensions can be prepared from sterile powders, granules, andtablets of the kind previously described.

Topical formulations, including those that are useful for transdermaldrug release, are well-known to those of skill in the art and aresuitable in the context of the disclosure for application to skin.Topically applied compositions are generally in the form of liquids,creams, pastes, lotions and gels. Topical administration includesapplication to the oral mucosa, which includes the oral cavity, oralepithelium, palate, gingival, and the nasal mucosa. In some embodiments,the composition contains at least one active component and a suitablevehicle or carrier. It may also contain other components, such as ananti-irritant. The carrier can be a liquid, solid or semi-solid. Inembodiments, the composition is an aqueous solution. Alternatively, thecomposition can be a dispersion, emulsion, gel, lotion or cream vehiclefor the various components. In one embodiment, the primary vehicle iswater or a biocompatible solvent that is substantially neutral or thathas been rendered substantially neutral. The liquid vehicle can includeother materials, such as buffers, alcohols, glycerin, and mineral oilswith various emulsifiers or dispersing agents as known in the art toobtain the desired pH, consistency and viscosity. It is possible thatthe compositions can be produced as solids, such as powders or granules.The solids can be applied directly or dissolved in water or abiocompatible solvent prior to use to form a solution that issubstantially neutral or that has been rendered substantially neutraland that can then be applied to the target site. In embodiments of thedisclosure, the vehicle for topical application to the skin can includewater, buffered solutions, various alcohols, glycols such as glycerin,lipid materials such as fatty acids, mineral oils, phosphoglycerides,collagen, gelatin and silicone based materials.

Formulations suitable for oral administration can consist of (a) liquidsolutions, such as a therapeutically effective amount of the inventivecompound dissolved in diluents, such as water, saline, or orange juice,(b) capsules, sachets, tablets, lozenges, and troches, each containing apredetermined amount of the active ingredient, as solids or granules,(c) powders, (d) suspensions in an appropriate liquid, and (e) suitableemulsions. Liquid formulations may include diluents, such as water andalcohols, for example, ethanol, benzyl alcohol, and the polyethylenealcohols, either with or without the addition of a pharmaceuticallyacceptable surfactant, suspending agent, or emulsifying agent. Capsuleforms can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers,such as lactose, sucrose, calcium phosphate, and corn starch. Tabletforms can include one or more of lactose, sucrose, mannitol, cornstarch, potato starch, alginic acid, microcrystalline cellulose, acacia,gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium,talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid,and other excipients, colorants, diluents, buffering agents,disintegrating agents, moistening agents, preservatives, flavoringagents, and pharmacologically compatible excipients. Lozenge forms cancomprise the active ingredient in a flavor, usually sucrose and acaciaor tragacanth, as well as pastilles comprising the active ingredient inan inert base, such as gelatin and glycerin, or sucrose and acacia,emulsions, gels, and the like containing, in addition to the activeingredient, such excipients as are known in the art.

The compound or salt of the present disclosure, alone or in combinationwith other suitable components, can be made into aerosol formulations tobe administered via inhalation. The compounds are preferably supplied infinely divided form along with a surfactant and propellant. Typicalpercentages of active compound are 0.01%-20% by weight, preferably1%-10%. The surfactant must, of course, be nontoxic, and preferablysoluble in the propellant. Representative of such surfactants are theesters or partial esters of fatty acids containing from 6 to 22 carbonatoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic,linolenic, olesteric and oleic acids with an aliphatic polyhydricalcohol or its cyclic anhydride. Mixed esters, such as mixed or naturalglycerides may be employed. The surfactant may constitute 0.1%-20% byweight of the composition, preferably 0.25%-5%. The balance of thecomposition is ordinarily propellant. A carrier can also be included asdesired, e.g., lecithin for intranasal delivery. These aerosolformulations can be placed into acceptable pressurized propellants, suchas dichlorodifluoromethane, propane, nitrogen, and the like. They alsomay be formulated as pharmaceuticals for non-pressured preparations,such as in a nebulizer or an atomizer. Such spray formulations may beused to spray mucosa.

Additionally, the compound or salt of the present disclosure may be madeinto suppositories by mixing with a variety of bases, such asemulsifying bases or water-soluble bases. Formulations suitable forvaginal administration may be presented as pessaries, tampons, creams,gels, pastes, foams, or spray formulas containing, in addition to theactive ingredient, such carriers as are known in the art to beappropriate.

It will be appreciated by one of ordinary skill in the art that, inaddition to the aforedescribed pharmaceutical compositions, the compoundor salt of the present disclosure may be formulated as inclusioncomplexes, such as cyclodextrin inclusion complexes, or liposomes.Liposomes serve to target the compounds to a particular tissue, such aslymphoid tissue or cancerous hepatic cells. Liposomes can also be usedto increase the half-life of the inventive compound. Liposomes useful inthe present disclosure include emulsions, foams, micelles, insolublemonolayers, liquid crystals, phospholipid dispersions, lamellar layersand the like. In these preparations, the active agent to be delivered isincorporated as part of a liposome, alone or in conjunction with asuitable chemotherapeutic agent. Thus, liposomes filled with a desiredinventive compound or salt thereof, can be directed to the site of aspecific tissue type, hepatic cells, for example, where the liposomesthen deliver the selected compositions. Liposomes for use in thedisclosure are formed from standard vesicle-forming lipids, whichgenerally include neutral and negatively charged phospholipids and asterol, such as cholesterol. The selection of lipids is generally guidedby consideration of, for example, liposome size and stability of theliposomes in the blood stream. A variety of methods are available forpreparing liposomes, as described in, for example, Szoka et al., Ann.Rev. Biophys. Bioeng., 9, 467 (1980), and U.S. Pat. Nos. 4,235,871,4,501,728, 4,837,028, and 5,019,369. For targeting to the cells of aparticular tissue type, a ligand to be incorporated into the liposomecan include, for example, antibodies or fragments thereof specific forcell surface determinants of the targeted tissue type. A liposomesuspension containing a compound or salt of the present disclosure maybe administered intravenously, locally, topically, etc. in a dose thatvaries according to the mode of administration, the agent beingdelivered, and the stage of disease being treated.

The disclosure further provides a method for therapeutic intervention ina facet of mammalian health that is mediated by a mammalian relaxinreceptor 1 comprising administering to a mammal in need thereof atherapeutically effective amount of a compound or salt thereofrepresented by Formula (I):

wherein A is 1,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, or—CH₂CH₂—, wherein the 1,2-phenylenyl, 1,2-heteroarylenyl, or1,2-heterocyclyl are optionally substituted with one or moresubstituents independently selected from halo, CF₃, alkyl, alkyloxy,haloalkyl, haloalkoxy —SR₇, —SOR₇, —SO₂R₇, —SCF₃, and SO₂CF₃,

R₁ is —NHCOR₃, R₄, —NHR₅, or —OR₆,

R₂ is alkyl, cycloalkyl, heteroarylalkyl, or phenyl, which areoptionally substituted with one or more substituents independentlyselected from halo, CF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkyloxy,C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy aryl, haloalkylaryl,heterocyclylalkyl, —SR₇, —SOR₇, —SO₂R₇, —SCF₃, —NO₂, —CN, and —SO₂CF₃,

R₃ is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, aryl, heteroaryl,arylalkyl, or phenyl, which are optionally substituted with one or moresubstituents selected from halo, CF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, —SO₂R₇,—SCF₃, —NO₂, —CN, and —SO₂CF₃,

R₄ is phenyl optionally substituted with alkyloxy, haloalkyloxy,arylalkyl, or arylalkyloxy,

R₅ is hydrogen, alkyl, alkylaryl, aryl, alkylcycloalkyl, orcycloalkylalkyl which are optionally substituted with one or moresubstituents independently selected from alkyloxy and trifluoromethyl,

R₆ is alkyl optionally substituted with alkylamino, dialkylamino,alkyloxy, and heteroaryl,

and R₇ is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀haloalkyl, orC₁-C₁₀haloalkoxy.

In accordance with certain embodiments, R₂ is phenyl substituted with—SO₂CF₃, —SCF₃, or —CF₃.

In accordance with certain embodiments, A is 1,2-phenylene optionallysubstituted with one or more substituents independently selected fromhalo, —CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, —SR₇, —SOR₇, —SO₂R₇,—SCF₃, and —SO₂CF₃.

In accordance with certain embodiments, R₁ is —NHCOR₃, wherein R₃ isphenyl substituted with a substituent selected from —CF₃, C₁-C₁₀ alkyl,C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, alkyloxyalkyloxy,dimethylaminoalkyloxy, —SR₇, —SOR₇, —SO₂R⁷, —SCF₃, and —SO₂CF₃.

In accordance with certain preferred embodiments, R₃ is2-(C₁-C₁₀)alkyloxyphenyl.

In accordance with certain preferred embodiments, R₂ is phenylsubstituted with a substituent selected from —CF₃, C₁-C₁₀ alkyl, C₁-C₁₀alkyloxy, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy —SR₇, —SOR₇, —SO₂R₇, —SCF₃,and —SO₂CF₃.

In certain preferred embodiments, the compound is selected from thegroup consisting of:

In accordance with certain embodiments, R₁ is R₄, wherein R₄ is2-(C₁-C₁₀)alkyloxyphenyl or 2-(C₁-C₁₀)haloalkyloxyphenyl.

In accordance with certain preferred embodiments, R₁ is —NHR₅, whereinR₅ is aryl optionally substituted with one or more substituentsindependently selected from alkyloxy and trifluoromethyl.

In accordance with certain embodiments, R₁ is —OR₆, wherein R₆ is alkyloptionally substituted with alkylamino, dialkylamino, alkyloxy, andheteroaryl.

In accordance with certain embodiments, A is 1,2-heteroarylenyloptionally substituted with one or more substitutents independentlyselected from halo, —CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy —SR₇,—SOR₇, —SO₂R₇, —SCF₃, and —SO₂CF₃.

In accordance with certain preferred embodiments, A is selected from

In accordance with certain preferred embodiments, R₁ is —NHCOR₃, whereinR₃ is phenyl substituted with a substituent selected from independently—CF₃, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy,—SR₇, —SOR₇, —SO₂R₇, —SCF₃, and —SO₂CF₃.

In accordance with certain preferred embodiments, R3 is2-(C₁-C₁₀)alkyloxyphenyl or 2-(C₁-C₁₀)haloalkyloxyphenyl.

In certain preferred embodiments, wherein the compound is selected fromthe group consisting of:

In accordance with certain embodiments, A is —CH₂CH₂—.

In accordance with certain embodiments, wherein R₁ is —NHCOR₃, whereinR₃ is phenyl substituted with a substituent selected from —CF₃, C₁-C₁₀alkyl, C₁-C₁₀ alkyloxy, C₁-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇,—SO₂R₇, —SCF₃, and —SO₂CF₃.

In accordance with certain embodiments, R3 is 2-(C₁-C₁₀)alkyloxyphenylor 2-(C₁-C₁₀)haloalkyloxyphenyl.

In accordance with a particular embodiment, the compound is:

The facet of mammalian health can be any disease, disorder, or aspect ofmammalian health that is mediated by a mammalian relaxin receptor 1.Examples of facets of mammalian health, wherein the mammal is a human,that are mediated by a mammalian relaxin receptor 1, wherein themammalian relaxin receptor 1 is a human relaxin receptor 1, aredisclosed in, e.g., E. T. Van Der Westhuizen et al., Current DrugTargets 2007, 8, 91-104; U.S. Pat. No. 8,053,411; and U.S. PatentApplication Publication 2011/0177998, the discloses of which areincorporated herein.

The mammal can be any suitable mammal. Examples of suitable mammalsinclude, but are not limited to, the order Rodentia, such as mice, andthe order Logomorpha, such as rabbits. It is preferred that the mammalsare from the order Camivora, including Felines (cats) and Canines(dogs). It is more preferred that the mammals are from the orderArtiodactyla, including Bovines (cows) and Swines (pigs) or of the orderPerssodactyla, including Equines (horses). It is most preferred that themammals are of the order Primates, Ceboids, or Simioids (monkeys) or ofthe order Anthropoids (humans and apes). An especially preferred mammalis the human. Furthermore, the subject can be the unborn offspring ofany of the forgoing hosts, especially mammals (e.g., humans), in whichcase any screening of the subject or cells of the subject, oradministration of compounds to the subject or cells of the subject, canbe performed in utero.

The mammalian relaxin receptor 1 can be any suitable mammalian relaxinreceptor 1. Typically, the mammalian relaxin receptor 1 is a relaxinreceptor 1 that exists in the particular mammal being treated.

In some embodiments, the facet of mammalian health is a facet of humanhealth. In these embodiments, the mammalian relaxin receptor 1 is ahuman relaxin receptor 1.

In an embodiment, the facet of mammalian health is cardiovasculardisease. Non-limiting examples of cardiovascular disease include acuteheart failure, myocardial ischemia-reperfusion injury, cardiac fibrosis,acute congestive heart failure, cerebrovascular disease and stroke,post-infarction heart, cardiac anaphylaxis, cerebral ischemia (stroke),intestinal ischemia-reperfusion injury, systemic and pulmonaryhypertension, vascular inflammation, hypertension, high blood pressure;left ventricular hypertrophy (LVH); vasodilation; renal hypertension;diuresis; nephritis; natriuresis; scleroderma renal crisis; anginapectoris (stable and unstable); myocardial infarction; heart attack;coronary artery disease; coronary heart disease; cardiac arrhythmias;atrial fibrillation; portal hypertension; raised intraocular pressure;vascular restenosis; chronic hypertension; valvular disease; myocardialischemia; acute pulmonary edema; acute coronary syndrome; hypertensiveretinopathy; hypertensive pregnancy sickness; Raynaud's phenomenon;erectile dysfunction, glaucoma, and preeclampsia.

In an embodiment, the facet of mammalian health is dyspnea associatedwith acute heart failure in a human subject, wherein said subject hasdyspnea associated with acute heart failure and is in a hypertensive ornormotensive state at the onset of said administering.

In an embodiment, the facet of mammalian health is acute decompensatedheart failure, wherein the method is effective to reduce in-hospitalworsening of said acute decompensated heart failure in said subject. Ina preferred embodiment, the in-hospital worsening of said acutedecompensated heart failure comprises one or more of worsening dyspnea,need for additional therapy to treat said heart failure, need formechanical support of breathing, and need for mechanical support ofblood pressure. In another preferred embodiment, the method furthercomprises a reduction in the risk of death or rehospitalization of saidsubject.

In an embodiment, the facet of mammalian health is fibrotic disease. Inselected embodiments, the fibrotic disease is selected from the group ofbut not limited to pulmonary fibrosis, renal tubulointerstitialfibrosis, mesangial proliferative nephritis, hepatic fibrosis(cirrhosis) alcohol and non-alcohol related (including viral infectionsuch as HAV, HBV and HCV); fibromatosis; granulomatous lung disease;glomerulonephritis, myocardial scarring following infarction;endometrial fibrosis and endometriosis, polycystic kidney disease,scleroderma and systemic sclerosis, keloids, arthritis, autoimmunedisorder, inflammatory condition associated with infection, skeletalmuscle injuries, conditions involving tissue remodeling followinginflammation or ischemia-reperfusion injury and is selected fromendomyocardial and cardiac fibrosis; mediastinal fibrosis;retroperitoneal fibrosis; fibrosis of the spleen; fibrosis of thepancreas; wound healing whether by injury or surgical procedures,diabetes related wound fibrosis.

In an embodiment, the facet of mammalian health is respiratory diseaseselected from asthma, bronchial disease, lung diseases, chronicobstructive pulmonary disease (COPD), Acute Respiratory DistressSyndrome (ARDS), severe acute respiratory syndrome (SARS), Fibrosisrelated Asthma, and cystic fibrosis.

In an embodiment, the facet of mammalian health is skin disease selectedfrom dermal repair, wound healing; burns, erythemas, lesions, woundhealing following surgical procedures; skin or tissue lesions includinglesions induced by Psoriasis, Lupus and Kaposhi Sarcoma; Scleroderma,and collagenous diseases of the skin and skin tumors.

In an embodiment, the facet of mammalian health is female reproduction.In selected embodiments, the facet of female reproduction is selectedfrom in vitro fertilization, abnormal implantation, pre-term birth andinduction of labor, mammary functions and lactation disorders, plasmaosmolarity during pregnancy, uterine fibroids, abnormal endometrialangiogenesis; placental development defects; cervical ripening(softening); nipple development and disfunction; pregnancy relatedremodeling of the uterine tissue; endometriosis; preeclampsia;estrogenic and non-estrogenic related hormonal disorders; pre-termlabor; post term labor; and labor complications.

In an embodiment, the facet of mammalian health is male reproduction. Inparticular embodiments, the facet of male reproduction is selected fromsperm functions and fertilization.

In an embodiment, the facet of mammalian health is surgicaltransplantation of a liver.

In an embodiment, the facet of mammalian health is a cancer selectedfrom colon cancer, lung cancer, breast cancer, prostate cancer, braincancer, pancreatic cancer, ovarian cancer, kidney cancer, testicularcancer, bone cancer, osteosarcoma, liver cancer, melanoma, glioma,sarcoma, leukemia, or lymphoma, and wherein the cancer is invasive ormetastatic.

In an embodiment, the facet of mammalian health is enhancement of drugdelivery in the treatment of a solid cancer, in combination with achemotherapeutic treatment or radiation treatment of the cancer.

In an embodiment, the facet of mammalian health is orthodontic toothmovement.

In an embodiment, the facet of mammalian health is bone joint disease.

In an embodiment, the facet of mammalian health is selected fromosteoporosis; osteoarthritis; osteopetrosis; bone inconsistency;osteosarcoma; and cancer metastasis to the bone.

In an embodiment, the facet of mammalian health is diabetes mellitus.

In an embodiment, the facet of mammalian health is ischemia-reperfusioninjury associated with ischemic and post-ischemic events in organs andtissues and in a group of patients with thrombotic stroke; myocardialinfarction; angina pectoris; embolic vascular occlusions; peripheralvascular insufficiency; splanchnic artery occlusion; arterial occlusionby thrombi or embolisms, arterial occlusion by non-occlusive processessuch as following low mesenteric flow or sepsis; mesenteric arterialocclusion; mesenteric vein occlusion; ischemia-reperfusion injury to themesenteric microcirculation; ischemic acute renal failure;ischemia-reperfusion injury to the cerebral tissue; intestinalintussusception; hemodynamic shock; tissue dysfunction; organ failure;restenosis; atherosclerosis; thrombosis; platelet aggregation,ischemia-reperfusion injury following cardiac surgery; organ surgery;organ transplantation; angiography; cardiopulmonary and cerebralresuscitation.

In an embodiment, the facet of mammalian health is an inflammatorycondition associated with an infection, wherein the infection isselected from a viral infection caused by human immunodeficiency virus I(HIV-1) or HIV-2, acquired immune deficiency (AIDS), West Nileencephalitis virus, coronavirus, rhinovirus, influenza virus, denguevirus, HCV, HBV, HAV, hemorrhagic fever; an otological infection; severeacute respiratory syndrome (SARS), sepsis and sinusitis.

In an embodiment, the facet of mammalian health is kidney diseasesselected from diabetic nephropathy; glomerulosclerosis; nephropathies;renal impairment; scleroderma renal crisis and chronic renal failure.

In an embodiment, the facet of mammalian health is an angiogenesisrelated condition selected from retinal angiogenesis in a number ofmammalian ocular diseases such as diabetes mellitus, retinopathy ofprematury, and age-related macular degeneration, or cancer associatedangiogenesis in primary or metastatic cancer, including but not limitedto cancer of the prostate, brain, breast, colorectal, lung, ovarian,pancreatic, renal, cervical, melanoma, soft tissue sarcomas, lymphomas,head-and-neck, and glioblastomas.

In an embodiment, the facet of mammalian health is an inflammatorydisorder selected from gastritis, gout, gouty arthritis, arthritis,rheumatoid arthritis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, ulcers, chronic bronchitis, asthma, allergy, acutelung injury, pulmonary inflammation, airway hyper-responsiveness,vasculitis, septic shock and inflammatory skin disorders, including butnot limited to psoriasis, atopic dermatitis, eczema.

In an embodiment, the facet of mammalian health is an autoimmunedisorder is selected from multiple sclerosis, psoriasis, rheumatoidarthritis, systemic lupus erythematosus, ulcerative colitis, Crohn'sdisease, transplant rejection, immune disorders associated with grafttransplantation rejection, benign lymphocytic angiitis, lupuserythematosus, Hashimoto's thyroiditis, primary myxedema, Graves'disease, pernicious anemia, autoimmune atrophic gastritis, Addison'sdisease, insulin dependent diabetes mellitis, Good pasture's syndrome,myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmuneuveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia,primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis,Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixedconnective tissue disease, inflammatory rheumatism, degenerativerheumatism, extra-articular rheumatism, collagen diseases, chronicpolyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenilerheumatoid arthritis, periarthritis humeroscapularis, panarteriitisnodosa, progressive systemic scleroderma, arthritis uratica,dermatomyositis, muscular rheumatism, myositis, myogelosis, andchondrocalcinosis.

In an embodiment, the facet of mammalian health is an behavioralabnormality or disease.

“Therapeutic intervention in a facet of mammalian health that ismediated by a mammalian relaxin receptor 1” refers to a therapeuticintervention that ameliorates a sign or symptom of a disease orpathological condition after it has begun to develop. As used herein,the term “ameliorating,” with reference to a disease or pathologicalcondition, refers to any observable beneficial effect of the treatment.The beneficial effect can be evidenced, for example, by a delayed onsetof clinical symptoms of the disease in a susceptible subject, areduction in severity of some or all clinical symptoms of the disease, aslower progression of the disease, an improvement in the overall healthor well-being of the subject, or by other parameters well known in theart that are specific to the particular disease. Treatment ofcardiovascular disease can be evidenced, for example, by reduction ofblood pressure, an enhancement of vascular compliance, a reduction inclinical symptoms resulting from the cardiovascular disease, or otherparameters well known in the art that are specific to the cardiovasculardisease. The phrase “treating a disease” refers to inhibiting the fulldevelopment of a disease or condition, for example, in a subject who isat risk for a disease such as cardiovascular disease.

In other embodiments, the therapeutic intervention provides anenhancement in a desirable facet of mammalian health. In certainembodiments the therapeutic intervention provides an enhancement in adesirable facet of human health. For example, the therapeuticintervention can lead to improved outcomes in organ transplantation, inimprovements in female fertility such as increased success in in vitrofertilization, and the like.

One skilled in the art will appreciate that suitable methods ofutilizing a compound and administering it to a mammal for the treatmentor prevention of disease states which would be useful in the method ofthe present disclosure, are available. Although more than one route canbe used to administer a particular compound, a particular route canprovide a more immediate and more effective reaction than another route.Accordingly, the described methods are merely exemplary and are in noway limiting.

The dose administered to a mammal, particularly, a human, in accordancewith the present disclosure should be sufficient to effect the desiredresponse. Such responses include reversal or prevention of the badeffects of the disease for which treatment is desired or to elicit thedesired benefit. One skilled in the art will recognize that dosage willdepend upon a variety of factors, including the age, condition, and bodyweight of the mammal, as well as the source, particular type of thedisease, and extent of the disease in the human. The size of the dosewill also be determined by the route, timing and frequency ofadministration as well as the existence, nature, and extent of anyadverse side-effects that might accompany the administration of aparticular compound and the desired physiological effect. It will beappreciated by one of skill in the art that various conditions ordisease states may require prolonged treatment involving multipleadministrations.

Suitable doses and dosage regimens can be determined by conventionalrange-finding techniques known to those of ordinary skill in the art.Generally, treatment is initiated with smaller dosages that are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. The present inventive method typically willinvolve the administration of about 0.1 to about 300 mg of one or moreof the compounds described above per kg body weight of the mammal.

The therapeutically effective amount of the compound or compoundsadministered can vary depending upon the desired effects and the factorsnoted above. Typically, dosages will be between 0.01 mg/kg and 250 mg/kgof the subject's body weight, and more typically between about 0.05mg/kg and 100 mg/kg, such as from about 0.2 to about 80 mg/kg, fromabout 5 to about 40 mg/kg or from about 10 to about 30 mg/kg of thesubject's body weight. Thus, unit dosage forms can be formulated basedupon the suitable ranges recited above and the subject's body weight.The term “unit dosage form” as used herein refers to a physicallydiscrete unit of therapeutic agent appropriate for the subject to betreated.

Alternatively, dosages are calculated based on body surface area andfrom about 1 mg/m² to about 200 mg/m², such as from about 5 mg/m² toabout 100 mg/m² will be administered to the subject per day. Inparticular embodiments, administration of the therapeutically effectiveamount of the compound or compounds involves administering to thesubject from about 5 mg/m² to about 50 mg/m², such as from about 10mg/m² to about 40 mg/m² per day. It is currently believed that a singledosage of the compound or compounds is suitable, however atherapeutically effective dosage can be supplied over an extended periodof time or in multiple doses per day. Thus, unit dosage forms also canbe calculated using a subject's body surface area based on the suitableranges recited above and the desired dosing schedule.

The disclosure further provides a use of a compound or salt of thedisclosure in the manufacture of a medicament for therapeuticintervention in a facet of mammalian health that is mediated by amammalian relaxin receptor 1. The medicament typically is apharmaceutical composition as described herein.

The following examples further illustrate the disclosure but, of course,should not be construed as in any way limiting its scope.

General Methods for Chemistry. All air or moisture sensitive reactionswere performed under positive pressure of nitrogen with oven-driedglassware. Anhydrous solvents such as dichloromethane,N,N-dimethylformamide (DMF), acetonitrile, methanol and triethylaminewere purchased from Sigma-Aldrich (St. Louis, Mo.). Preparativepurification was performed on a Waters semi-preparative HPLC system(Waters Corp., Milford, Mass.). The column used was a Phenomenex LunaC₁₈ (5 micron, 30×75 mm; Phenomenex, Inc., Torrance, Calif.) at a flowrate of 45.0 mL/min. The mobile phase consisted of acetonitrile andwater (each containing 0.1% trifluoroacetic acid). A gradient of 10% to50% acetonitrile over 8 minutes was used during the purification.Fraction collection was triggered by UV detection at 220 nM. Analyticalanalysis was performed on an Agilent LC/MS (Agilent Technologies, SantaClara, Calif.). Method 1 (t₁): A 7-minute gradient of 4% to 100%acetonitrile (containing 0.025% trifluoroacetic acid) in water(containing 0.05% trifluoroacetic acid) was used with an 8-minute runtime at a flow rate of 1.0 mL/min. Method 2 (t₂): A 3-minute gradient of4% to 100% acetonitrile (containing 0.025% trifluoroacetic acid) inwater (containing 0.05% trifluoroacetic acid) was used with a 4.5-minuterun time at a flow rate of 1.0 mL/min. A Phenomenex Luna C₁₈ column (3micron, 3×75 mm) was used at a temperature of 50° C. Puritydetermination was performed using an Agilent diode array detector forboth Method 1 and Method 2. Mass determination was performed using anAgilent 6130 mass spectrometer with electrospray ionization in thepositive mode. ¹H NMR spectra were recorded on Varian 400 MHzspectrometers (Agilent Technologies, Santa Clara, Calif.). Chemicalshifts are reported in ppm with undeuterated solvent (DMSO-d₆ at 2.49ppm) as internal standard for DMSO-d₆ solutions. All of the analogstested in the biological assays have a purity of greater than 95% basedon both analytical methods. High resolution mass spectrometry wasrecorded on Agilent 6210 Time-of-Flight (TOF) LC/MS system. Confirmationof molecular formula was accomplished using electrospray ionization inthe positive mode with the Agilent Masshunter software (Version B.02).

General Protocol A. A solution of methyl or ethyl benzoate (0.191 mmol)and amine (0.383 mmol) in toluene (2.00 mL) was treated at roomtemperature with AlMe₃ (0.192 mL, 2.0 M in toluene, 0.384 mmol). Thereaction mixture was stirred overnight at 100° C. and then quenched with100 μL of water. The mixture was concentrated, re-dissolved in 2.00 mLof DMSO, filtered and purified via C₁₈ reverse phase HPLC to give thefinal product.

General Protocol B. A solution of carboxylic acid (0.178 mmol) in DMF(2.00 mL) was treated at room temperature with2-amino-N-(3-(trifluoromethyl)phenyl)benzamide (25.0 mg, 0.089 mmol)followed by EDC (17.1 mg, 0.089 mmol) and DMAP (10.9 mg, 0.089 mmol).The reaction mixture was stirred overnight at room temperature. Themixture was purified via C₁₈ reverse phase HPLC to give the finalproduct.

General Protocol C. A solution of2-amino-N-(3-(trifluoromethyl)phenyl)benzamide (50.0 mg, 0.178 mmol) indichloromethane (2.00 mL) and TEA (0.075 mL, 0.535 mmol) was treated atroom temperature with carbonyl chloride (0.357 mmol). The reactionmixture was stirred at room temperature for 2 h. The mixture wasconcentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified viaC₁₈ reverse phase HPLC to give the final product.

General Protocol D. A solution of carboxylic acid (0.357 mmol) in DMF(2.00 mL) was added DIPEA (0.093 mL, 0.535 mmol) and HATU (136 mg, 0.357mmol). The reaction mixture was stirred at room temperature for 5 min,followed by 2-amino-N-(3-(trifluoromethyl)phenyl)benzamide (50.0 mg,0.178 mmol). The reaction mixture was stirred overnight at roomtemperature, filtered and purified via C₁₈ reverse phase HPLC to givethe final product.

General Protocol E. A mixture of2-bromo-N-(3-(trifluoromethyl)phenyl)benzamide (50.0 mg, 0.145 mmol, 1.0equiv.) or N-(3-bromophenyl)-2-(cyclohexanecarboxamido)benzamide (100mg, 0.249 mmol, 1.0 equiv.), boronic acid or pinacol ester (2.0 equiv.)and Pd(PPh₃)₄ (0.05 equiv) in DMF (1.50 mL) and 2.0 N Na₂CO₃ (0.50 mL)aqueous solution was heated in μW at 100° C. for 30 min-1 h. Thereaction was cooled to room temperature, added a small portion ofSi-THIOL to get rid of Palladium. The reaction mixture was filtered andpurified via C₁₈ reverse phase HPLC to give the final product.

General Protocol F. 2-Iodo-N-(3-(trifluoromethyl)phenyl)benzamide (100mg, 0.256 mmol), amine (0.767 mmol), and CuCl (7.59 mg, 0.077 mmol) inDMF (1.00 mL) was stirred at room temperature for 15-30 min. Thereaction was treated with a small portion of Si-THIOL to get rid ofPalladium, filtered and purified via C₁₈ reverse phase HPLC to give thefinal product.

General Protocol G. A solution of thio-compound (0.255 mmol) indichloromethane (3.00 mL) was treated at room temperature with MCPBA(220 mg, 1.27 mmol). The reaction mixture was stirred overnight at roomtemperature. 10% aqueous NaHSO₃ solution was added to quench excessMCPBA and the mixture was stirred at room temperature for 15 min. Thereaction mixture was worked up with dichloromethane and water. Theorganic layer was separated, dried, concentrated, and purified via C₁₈reverse phase HPLC to give the final product.

General Protocol H. A tube was charged with CuI (0.1 equiv.),1,10-phenanthroline (0.2 equiv.), Cs₂CO₃ (2.0 equiv.), iodo substrate(1.0 equiv.) and alcohol (2.0 equiv.) in toluene (2.00 mL) under N₂. Thetube was sealed and the reaction mixture was stirred at 110° C. for 24h. The resulting mixture was cooled to room temperature and treated witha small portion of Si-THIOL to get rid of copper. The mixture wasconcentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified viaC₁₈ reverse phase HPLC to give the final product

Example 1

This example illustrates a synthesis of Methyl2-(cyclohexanecarboxamido)benzoate (XJB05-077, NCGC00189490-01). Asolution of methyl 2-aminobenzoate (3.00 g, 19.9 mmol) indichloromethane (100 mL) and triethylamine (8.30 mL, 59.5 mmol) wastreated at 0° C. with cyclohexanecarbonyl chloride (2.70 mL, 19.9 mmol).The reaction was stirred at 0° C. for 2 h and room temperature foradditional 2 h. The reaction mixture was concentrated and purified viasilica gel chromatography using a gradient of 0-40% of EtOAc in hexanesto give 5.00 g (96%) of the title product as a white solid. LC-MSRetention Time: t₁ (Method 1)=6.453 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.65 (s, 1H), 8.31 (dd, J=8.5, 1.1 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz,1H), 7.57 (ddd, J=8.6, 7.2, 1.7 Hz, 1H), 6.87-7.29 (m, 1H), 3.83 (s,3H), 2.31 (tt, J=11.3, 3.5 Hz, 1H), 1.88 (dd, J=12.9, 2.5 Hz, 2H), 1.73(ddd, J=12.4, 3.3, 3.1 Hz, 2H), 1.55-1.67 (m, 1H), 1.08-1.47 (m, 5H).

Example 2

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)benzoic acid (XJB05-087, NCGC00189489-01). Asolution of methyl 2-(cyclohexanecarboxamido)benzoate (4.00 g, 15.3mmol) in MeOH (100 mL) was treated at room temperature with 4.0 N NaOHaqueous solution (40.0 mL, 153 mmol). The reaction mixture was stirredat room temperature for 1 h. MeOH was removed by rotavapor and themixture was cooled in ice-bath and acidified with 5.0 N HCl until whiteprecipitation was appeared. The white precipitation was filtered andwashed with water to give 3.60 g (95%) of the title product as a whitesolid. LC-MS Retention Time: t₁ (Method 1)=5.345 min.

Example 3

This example illustrates a synthesis of tert-Butyl2-(3-(trifluoromethyl)phenylcarbamoyl)phenylcarbamate (XJB05-088,NCGC00189488-01). A solution of 2-(tert-butoxycarbonylamino)benzoic acid(3.00 g, 12.6 mmol) and 3-(trifluoromethyl)aniline (2.36 mL, 19.0 mmol)in dichloromethane (75.0 mL) was treated at room temperature with DMAP(1.55 g, 12.6 mmol) and EDC (4.85 g, 25.3 mmol) and stirred at roomtemperature for 24 h. The reaction mixture was concentrated and purifiedvia silica gel chromatography using a gradient of 0-100% ofdichloromethane in hexanes followed by 10% of EtOAc in dichloromethaneto give 2.20 g (46%) of the title product as a white solid. LC-MSRetention Time: t₁ (Method 1)=7.042 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.64 (s, 1H), 9.75 (s, 1H), 8.14 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.94(d, J=9.2 Hz, 1H), 7.77 (dd, J=7.9, 1.5 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H),7.51 (ddd, J=8.5, 7.2, 1.5 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.16 (td,J=7.6, 1.1 Hz, 1H), 1.41 (s, 9H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.20 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₁₉H₂₀F₃N₂O₃,381.1421; found 381.1426.

Example 4

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-phenylbenzamide (XJB06-001,NCGC00189487-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.326 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.54 (s, 1H), 10.37 (s, 1H), 8.23 (dd, J=8.2, 1.0Hz, 1H), 7.77 (dd, J=7.9, 1.5 Hz, 1H), 7.63-7.71 (m, 2H), 7.49 (ddd,J=8.4, 7.2, 1.6 Hz, 1H), 7.28-7.41 (m, 2H), 7.19 (td, J=7.6, 1.3 Hz,1H), 7.07-7.14 (m, 1H), 2.17-2.34 (m, 1H), 1.76-1.88 (m, 2H), 1.69 (ddd,J=12.5, 3.4, 3.2 Hz, 2H), 1.59 (d, J=12.1 Hz, 1H), 1.03-1.43 (m, 5H);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₃N₂O₀, 323.1754; found 323.1758.

Example 5

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB06-002, NCGC00189486-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.910 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.61 (s, 1H), 10.27 (s, 1H), 8.12 (s, 1H),8.07 (dd, J=8.4, 1.0 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.74 (dd, J=7.7,1.5 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.47-7.54 (m, 1H), 7.44 (dt, J=7.7,0.8 Hz, 1H), 7.21 (td, J=7.5, 1.2 Hz, 1H), 2.22-2.35 (m, 1H), 1.79 (dd,J=13.3, 2.3 Hz, 2H), 1.68 (ddd, J=12.3, 3.1, 2.9 Hz, 2H), 1.58 (ddd,J=11.9, 3.2, 3.0 Hz, 1H), 1.00-1.40 (m, 5H); ¹⁹F NMR (376 MHz, DMSO-d₆)δ ppm −61.30 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₂F₃N₂O₂,391.1628; found 391.1632.

Example 6

This example illustrates a synthesis ofN-(3-Bromophenyl)-2-(cyclohexanecarboxamido)benzamide (XJB06-005,NCGC00189485-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.904 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.47 (s, 1H), 10.31 (s, 1H), 8.11 (dd, J=8.4, 1.0Hz, 1H), 7.94-8.04 (m, 1H), 7.72 (dd, J=7.8, 1.6 Hz, 1H), 7.64 (ddd,J=6.7, 2.3, 2.2 Hz, 1H), 7.49 (ddd, J=8.4, 7.2, 1.6 Hz, 1H), 7.24-7.35(m, 2H), 7.19 (td, J=7.6, 1.2 Hz, 1H), 2.21-2.37 (m, 1H), 1.80 (d,J=11.5 Hz, 2H), 1.69 (dt, J=12.2, 3.2 Hz, 2H), 1.59 (d, J=12.5 Hz, 1H),1.07-1.42 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂BrN₂O₂,401.0859; found 401.0859.

Example 7

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-fluorophenyl)benzamide (XJB06-006,NCGC00189484-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.529 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.51 (s, 1H), 10.33 (s, 1H), 8.12 (dd, J=8.3, 1.1Hz, 1H), 7.73 (dd, J=7.7, 1.5 Hz, 1H), 7.64 (dt, J=11.7, 2.3 Hz, 1H),7.43-7.55 (m, 2H), 7.37 (td, J=8.2, 6.7 Hz, 1H), 7.20 (td, J=7.5, 1.2Hz, 1H), 6.82-6.98 (m, 1H), 2.21-2.35 (m, 1H), 1.81 (d, J=11.5 Hz, 2H),1.69 (dt, J=12.4, 3.3 Hz, 2H), 1.59 (d, J=11.7 Hz, 1H), 1.02-1.43 (m,5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −112.20-−112.29 (m, 1 F); HRMS(ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂FN₂O₂, 341.1660; found 341.1660.

Example 8

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-methoxyphenyl)benzamide (XJB06-007,NCGC00189483-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.344 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.47 (s, 1H), 10.33 (s, 1H), 8.20 (dd, J=8.4, 1.0Hz, 1H), 7.74 (dd, J=7.8, 1.4 Hz, 1H), 7.49 (ddd, J=8.4, 7.2, 1.6 Hz,1H), 7.33 (t, J=2.2 Hz, 1H), 7.13-7.30 (m, 3H), 6.69 (ddd, J=7.8, 2.5,1.4 Hz, 1H), 3.73 (s, 3H), 2.26 (tt, J=11.3, 3.6 Hz, 1H), 1.82 (dd,J=12.5, 2.7 Hz, 2H), 1.69 (ddd, J=12.4, 3.1, 2.8 Hz, 2H), 1.51-1.64 (m,1H), 1.02-1.41 (n, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₅N₂O₃,353.1860; found 353.1856.

Example 9

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-m-tolylbenzamide (XJB06-008,NCGC00189482-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.632 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.54 (s, 1H), 10.30 (s, 1H), 8.24 (dd, J=8.3, 1.1Hz, 1H), 7.76 (dd, J=7.8, 1.4 Hz, 1H), 7.38-7.54 (m, 3H), 7.10-7.31 (m,2H), 6.93 (dddd, J=7.5, 1.5, 1.1, 0.8 Hz, 1H), 2.29 (s, 3H), 2.19-2.35(m, 1H), 1.82 (dd, J=12.8, 2.6 Hz, 2H), 1.69 (dt, J=12.4, 3.4 Hz, 2H),1.59 (d, J=12.3 Hz, 1H), 1.04-1.42 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₁H₂₅N₂O₂, 337.1911; found 337.1908.

Example 10

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-nitrophenyl)benzamide (XJB06-009,NCGC00189481-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.392 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.76 (s, 1H), 10.26 (s, 1H), 8.69 (t, J=2.2 Hz,1H), 8.01-8.15 (m, 2H), 7.95 (ddd, J=8.3, 2.3, 1.0 Hz, 1H), 7.75 (dd,J=7.8, 1.6 Hz, 1H), 7.64 (t, J=8.2 Hz, 1H), 7.46-7.56 (m, 1H), 7.22 (td,J=7.6, 1.2 Hz, 1H), 2.19-2.35 (m, 1H), 1.79 (dd, J=12.5, 2.5 Hz, 2H),1.68 (dt, J=12.3, 3.1 Hz, 2H), 1.58 (d, J=12.5 Hz, 1H), 1.03-1.43 (m,5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂N₃O₄, 368.1605; found368.1616.

Example 11

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(4-(trifluoromethyl)phenyl)benzamide(XJB06-012, NCGC00189480-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.943 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1H), 10.29 (s, 1H), 8.09 (dd,J=8.4, 1.0 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H), 7.74 (dd, J=7.8, 1.4 Hz,1H), 7.71 (d, J=8.4 Hz, 2H), 7.51 (ddd, J=8.4, 7.3, 1.6 Hz, 1H), 7.21(td, J=7.6, 1.2 Hz, 1H), 2.18-2.35 (m, 1H), 1.80 (dd, J=12.7, 2.9 Hz,2H), 1.68 (dt, J=12.2, 3.4 Hz, 2H), 1.59 (d, J=11.9 Hz, 1H), 1.01-1.43(m, 5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −60.26 (s, 3 F); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₁H₂₂F₃N₂O₂, 391.1628; found 391.1628.

Example 12

This example illustrates a synthesis ofN-(4-Bromophenyl)-2-(cyclohexanecarboxamido)benzamide (XJB06-013,NCGC00189479-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.893 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.46 (s, 1H), 10.41 (s, 1H), 8.16 (dd, J=8.2, 1.0Hz, 1H), 7.74 (dd, J=7.8, 1.6 Hz, 1H), 7.60-7.69 (m, 2H), 7.50-7.56 (m,2H), 7.46-7.50 (m, 1H), 7.19 (td, J=7.5, 1.2 Hz, 1H), 2.18-2.34 (m, 1H),1.81 (dd, J=12.1, 3.3 Hz, 2H), 1.69 (dt, J=12.3, 3.1 Hz, 2H), 1.59 (d,J=11.9 Hz, 1H), 1.06-1.42 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₀H₂₂BrN₂O₂, 401.0859; found 401.0858.

Example 13

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(4-fluorophenyl)benzamide (XJB06-014,NCGC00189478-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.413 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.52 (s, 1H), 10.41 (s, 1H), 8.22 (dd, J=8.3, 0.9Hz, 1H), 7.76 (dd, J=7.8, 1.4 Hz, 1H), 7.62-7.73 (m, 2H), 7.49 (ddd,J=8.4, 7.2, 1.6 Hz, 1H), 7.10-7.28 (m, 3H), 2.17-2.35 (m, 1H), 1.82 (dd,J=12.9, 2.5 Hz, 2H), 1.69 (dt, J=12.3, 3.3 Hz, 2H), 1.53-1.63 (m, 1H),0.97-1.43 (m, 5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −118.31-−118.38 (m,1 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂FN₂O₂, 341.1660; found341.1659.

Example 14

This example illustrates a synthesis of2-(cyclohexanecarboxamido)-N-p-tolylbenzamide (XJB06-015,NCGC00189477-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.636 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.61 (s, 1H), 10.30 (s, 1H), 8.26 (dd, J=8.2, 0.8Hz, 1H), 7.77 (dd, J=7.8, 1.4 Hz, 1H), 7.52-7.59 (m, 2H), 7.48 (ddd,J=8.4, 7.2, 1.6 Hz, 1H), 7.18 (dd, J=7.8, 1.2 Hz, 1H), 7.11-7.17 (m,2H), 2.26 (s, 3H), 2.16-2.36 (m, 1H), 1.82 (dd, J=13.0, 2.1 Hz, 2H),1.69 (ddd, J=12.2, 3.3, 3.1 Hz, 2H), 1.51-1.64 (m, 1H), 1.02-1.47 (m,5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₅N₂O₂, 337.1911; found337.1916.

Example 15

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(4-methoxyphenyl)benzamide (XJB06-016,NCGC00189476-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.243 min; ¹H NMR (400MHz, DMSO-d6) δ ppm 10.71 (s, 1H), 10.27 (s, 1H), 8.29 (dd, J=8.3, 0.9Hz, 1H), 7.78 (dd, J=7.8, 1.4 Hz, 1H), 7.52-7.63 (m, 2H), 7.48 (ddd,J=8.4, 7.3, 1.5 Hz, 1H), 7.17 (td, J=7.5, 1.2 Hz, 1H), 6.83-7.02 (m,2H), 3.73 (s, 3H), 2.25 (tt, J=11.2, 3.4 Hz, 1H), 1.77-1.93 (m, 2H),1.70 (ddd, J=12.3, 3.2, 2.9 Hz, 2H), 1.52-1.64 (m, 1H), 1.00-1.47 (m,5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₅N₂O₃, 353.1860; found353.1857.

Example 16

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(4-nitrophenyl)benzamide (XJB06-017,NCGC00189475-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.408 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.85 (s, 1H), 10.17 (s, 1H), 8.16-8.32 (m, 2H),7.85-8.06 (m, 3H), 7.72 (dd, J=7.8, 1.4 Hz, 1H), 7.43-7.58 (m, 1H), 7.22(td, J=7.5, 1.2 Hz, 1H), 2.27 (tt, J=11.2, 3.5 Hz, 1H), 1.72-1.88 (m,2H), 1.68 (ddd, J=9.0, 6.1, 2.7 Hz, 2H), 1.52-1.63 (m, 1H), 0.99-1.45(m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂N₃O₄, 368.1605; found368.1605.

Example 17

This example illustrates a synthesis ofN-(2-Bromophenyl)-2-(cyclohexanecarboxamido)benzamide (XJB06-027,NCGC00189474-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.689 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.91 (s, 1H), 10.26 (s, 1H), 8.36 (dd, J=8.4, 1.0Hz, 1H), 7.93 (dd, J=7.8, 1.4 Hz, 1H), 7.71 (dd, J=8.0, 1.4 Hz, 1H),7.49-7.59 (m, 2H), 7.44 (td, J=7.6, 1.4 Hz, 1H), 7.22-7.27 (m, 1H), 7.20(td, J=7.6, 1.2 Hz, 1H), 2.24 (tt, J=11.3, 3.5 Hz, 1H), 1.82 (dd,J=12.6, 2.4 Hz, 2H), 1.69 (ddd, J=12.5, 3.2, 2.9 Hz, 2H), 1.51-1.64 (m,1H), 1.05-1.45 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂BrN₂O₂,401.0859; found 401.0863.

Example 18

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(2-fluorophenyl)benzamide (XJB06-028,NCGC00189473-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.305 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.85 (br. s., 1H), 10.28 (s, 1H), 8.34 (dd, J=8.4,1.0 Hz, 1H), 7.88 (dd, J=7.8, 1.4 Hz, 1H), 7.42-7.64 (m, 2H), 7.24-7.34(m, 2H), 7.13-7.24 (m, 2H), 2.24 (tt, J=11.2, 3.5 Hz, 1H), 1.76-1.86 (m,2H), 1.64-1.75 (m, 2H), 1.52-1.64 (m, 1H), 0.99-1.43 (m, 5H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ ppm −120.74-−120.85 (m, 1 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₀H₂₂FN₂O₂, 341.1660; found 341.1656.

Example 19

This example illustrates a synthesis of2-(cyclohexanecarboxamido)-N-o-tolylbenzamide (XJB06-029,NCGC00189472-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.401 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.00 (s, 1H), 10.09 (s, 1H), 8.38 (dd, J=8.4, 1.2Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.51 (ddd, J=8.6, 7.2, 1.7 Hz, 1H),7.25-7.35 (m, 2H), 7.10-7.25 (m, 3H), 2.21 (s, 3H), 2.16-2.28 (m, 1H),1.77-1.91 (m, 2H), 1.69 (dt, J=12.4, 3.5 Hz, 2H), 1.53-1.65 (m, 1H),0.99-1.44 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₅N₂O₂,337.1911; found 337.1912.

Example 20

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(2-nitrophenyl)benzamide (XJB06-031,NCGC00189471-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.550 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.85 (s, 1H), 10.44 (s, 1H), 8.25 (dd, J=8.4, 1.2Hz, 1H), 8.01 (dd, J=8.2, 1.6 Hz, 1H), 7.84 (dd, J=7.8, 1.6 Hz, 1H),7.67-7.80 (m, 2H), 7.54 (ddd, J=8.6, 7.3, 1.6 Hz, 1H), 7.44 (ddd, J=8.4,6.7, 2.0 Hz, 1H), 7.23 (td, J=7.6, 1.3 Hz, 1H), 2.22 (tt, J=11.4, 3.5Hz, 1H), 1.80 (d, J=14.7 Hz, 2H), 1.68 (ddd, J=12.3, 3.4, 3.3 Hz, 2H),1.59 (d, J=11.9 Hz, 1H), 1.05-1.41 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₀H₂₂N₃O₄, 368.1605; found 368.1605.

Example 21

This example illustrates a synthesis of2-Amino-N-(3-(trifluoromethyl)phenyl)benzamide (XJB06-036,NCGC00189470-01). A solution of tert-butyl2-(3-(trifluoromethyl)phenylcarbamoyl)phenylcarbamate (2.11 g, 5.55mmol) in dichloromethane (15.0 mL) was treated at 0° C. with TFA (5.34mL, 69.3 mmol). The reaction mixture was stirred at 0° C. for 1 h androom temperature for additional 2 h. The reaction mixture wasconcentrated and re-dissolved in dichloromethane and washed withsaturated Na₂CO₃ aqueous solution. The organic layer was separated,dried and concentrated to give 1.45 g (99%) of the title compound as awhite solid. LC-MS Retention Time: t₁ (Method 1)=5.590 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.24 (s, 1H), 8.18 (t, J=2.2 Hz, 1H), 7.95 (ddd,J=8.4, 1.2, 1.0 Hz, 1H), 7.63 (dd, J=8.0, 1.6 Hz, 1H), 7.54 (t, J=8.3Hz, 1H), 7.34-7.43 (m, 1H), 7.19 (ddd, J=8.4, 7.0, 1.6 Hz, 1H), 6.74(dd, J=8.3, 1.3 Hz, 1H), 6.57 (ddd, J=8.1, 7.0, 1.2 Hz, 1H), 6.34 (br.s., 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.18 (s, 3 F).

Example 22

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(2-(trifluoromethyl)benzyl)benzamide(XJB06-038, NCGC00189469-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.797 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.12 (s, 1H), 9.29 (t, J=5.9 Hz, 1H), 8.40(dd, J=8.4, 1.4 Hz, 1H), 7.82 (dd, J=7.9, 1.7 Hz, 1H), 7.73 (dt, J=7.8,0.8 Hz, 1H), 7.64 (t, J=7.3 Hz, 1H), 7.42-7.56 (m, 3H), 7.09-7.19 (m,1H), 4.65 (d, J=6.1 Hz, 2H), 2.21 (tt, J=11.2, 3.5 Hz, 1H), 1.76-1.88(m, 2H), 1.63-1.73 (m, 2H), 1.51-1.63 (m, 1H), 1.03-1.44 (m, 5H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ ppm −58.97 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₂H₂₄F₃N₂O₂, 405.1784; found 405.1790.

Example 23

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(furan-2-ylmethyl)benzamide (XJB06-039,NCGC00189468-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=5.946 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.24 (s, 1H), 9.19 (t, J=5.7 Hz, 1H), 8.40 (dd,J=8.4, 1.4 Hz, 1H), 7.72 (dd, J=7.8, 1.6 Hz, 1H), 7.56 (dd, J=1.9, 0.9Hz, 1H), 7.45 (ddd, J=8.5, 7.1, 1.6 Hz, 1H), 6.99-7.15 (m, 1H), 6.38(dd, J=3.2, 1.9 Hz, 1H), 6.22-6.33 (m, 1H), 4.45 (dd, J=5.6, 0.5 Hz,2H), 2.23 (tt, J=11.2, 3.5 Hz, 1H), 1.79-1.93 (m, 2H), 1.71 (dt, J=12.6,3.6 Hz, 2H), 1.54-1.67 (m, 1H), 1.03-1.47 (m, 5H); HRMS (ESI) m/z (M+H)⁺calcd. for C₁₉H₂₃N₂O₃, 327.1703; found 327.1708.

Example 24

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzamide(XJB06-040, NCGC00189467-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.825 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.51 (s, 1H), 10.44 (s, 1H), 8.14 (dd,J=8.3, 1.3 Hz, 1H), 8.07 (dd, J=6.8, 2.3 Hz, 1H), 7.81 (dd, J=7.8, 1.6Hz, 1H), 7.61-7.73 (m, 1H), 7.46-7.59 (m, 2H), 7.21 (td, J=7.6, 1.3 Hz,1H), 2.20-2.34 (m, 1H), 1.75-1.88 (m, 2 H), 1.68 (ddd, J=12.8, 3.1, 2.9Hz, 2H), 1.52-1.64 (m, 1H), 1.07-1.42 (n, 5H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −60.47 (s, 3 F), −119.15-−111.85 (n, 1 F); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₁H₂₁F₄N₂O₂, 409.1534; found 409.1534.

Example 25

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-(trifluoromethyl)benzyl)benzamide(XJB06-041, NCGC00189466-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.781 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.13 (s, 1H), 9.34 (t, J=6.1 Hz, 1H), 8.37(dd, J=8.4, 1.4 Hz, 1H), 7.76 (dd, J=7.9, 1.7 Hz, 1H), 7.66-7.70 (m,1H), 7.58-7.66 (m, 2H), 7.53-7.58 (m, 1H), 7.47 (ddd, J=8.5, 7.2, 1.7Hz, 1H), 7.13 (td, J=7.6, 1.3 Hz, 1H), 4.54 (d, J=5.9 Hz, 2H), 2.20 (tt,J=11.2, 3.5 Hz, 1H), 1.75-1.87 (m, 2H), 1.68 (dt, J=12.3, 3.2 Hz, 2H),1.53-1.64 (m, 1H), 1.02-1.42 (m, 5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.02 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₄F₃N₂O₂,405.1784; found 405.1790.

Example 26

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(thiophen-2-ylmethyl)benzamide (XJB06-042,NCGC00189465-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.211 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.21 (s, 1H), 9.22-9.73 (m, 1H), 8.40 (dd, J=8.4,1.4 Hz, 1H), 7.70 (dd, J=8.0, 1.6 Hz, 1H), 7.45 (ddd, J=8.5, 7.1, 1.6Hz, 1H), 7.38 (dd, J=5.1, 1.2 Hz, 1H), 7.10 (td, J=7.6, 1.3 Hz, 1H),6.99-7.05 (m, 1H), 6.94 (dd, J=5.1, 3.5 Hz, 1H), 4.61 (dd, J=5.9, 1.0Hz, 2H), 2.23 (tt, J=11.3, 3.4 Hz, 1H), 1.80-1.93 (m, 2H), 1.68-1.79 (m,2H), 1.56-1.68 (m, J=12.3, 3.4, 1.8, 1.8 Hz, 1H), 1.03-1.47 (m, 5H);HRMS (ESI) m/z (M+H)⁺ calcd. for C₁₉H₂₃N₂O₂S, 343.1475; found 343.1485.

Example 27

This example illustrates a synthesis of2-(cyclohexanecarboxamido)-N-(4-(trifluoromethyl)benzyl)benzamide(XJB06-043, NCGC00189464-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.763 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.15 (s, 1H), 9.36 (t, J=6.0 Hz, 1H), 8.38(dd, J=8.4, 1.4 Hz, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.68 (d, J=8.0Hz, 2H), 7.50-7.58 (m, 2H), 7.47 (ddd, J=8.6, 7.3, 1.6 Hz, 1H),7.08-7.20 (m, 1H), 4.54 (d, J=5.9 Hz, 2H), 2.20 (tt, J=11.2, 3.4 Hz,1H), 1.73-1.89 (m, 2H), 1.68 (ddd, J=12.5, 3.4, 3.1 Hz, 2H), 1.53-1.63(m, 1H), 1.02-1.43 (m, 5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −60.75 (s,3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₄F₃N₂O₂, 405.1784; found405.1789.

Example 28

This example illustrates a synthesis of2-(Cyclopentanecarboxamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB06-046, NCGC00189463-01). The title compound was prepared accordingto general protocol B. LC-MS Retention Time: t₁ (Method 1)=6.780 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.60 (s, 1H), 10.29 (s, 1H), 8.15 (t,J=2.2 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.73 (dd,J=7.8, 1.6 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.50 (ddd, J=8.5, 7.2, 1.6Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.21 (td, J=7.6, 1.3 Hz, 1H), 2.75(quin, J=8.0 Hz, 1H), 1.74-1.86 (m, 2H), 1.63-1.74 (m, 2H), 1.41-1.63(m, 4H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.21 (s, 3 F); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₀H₂₀F₃N₂O₂, 377.1471; found 377.1481.

Example 29

This example illustrates a synthesis of2-(2-Ethylbutanamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB06-047,NCGC00189462-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.751 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.60 (s, 1H), 10.25 (s, 1H), 8.15 (t, J=2.2 Hz,1H), 7.98 (dd, J=8.2, 1.4 Hz, 1H), 7.93 (ddd, J=8.2, 1.2, 1.0 Hz, 1H),7.72 (dd, J=7.7, 1.7 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.50 (ddd, J=8.4,7.1, 1.7 Hz, 1H), 7.38-7.47 (m, 1H), 7.23 (td, J=7.6, 1.3 Hz, 1H), 2.15(tt, J=8.8, 5.4 Hz, 1H), 1.30-1.62 (m, 4H), 0.74-0.86 (m, 6H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ ppm −61.23 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₀H₂₂F₃N₂O₂, 379.1628; found 379.1634.

Example 30

This example illustrates a synthesis of2-Pentanamido-N-(3-(trifluoromethyl)phenyl)benzamide (XJB06-048,NCGC00189461-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.546 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.61 (s, 1H), 10.19 (s, 1H), 8.17 (t, J=2.2 Hz,1H), 7.98 (dd, J=8.1, 1.1 Hz, 1H), 7.92 (ddd, J=8.2, 2.0, 0.8 Hz, 1H),7.71 (dd, J=7.7, 1.7 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.47-7.54 (m, 1H),7.39-7.47 (m, 1H), 7.21 (td, J=7.6, 1.3 Hz, 1H), 2.28 (t, J=7.4 Hz, 2H),1.43-1.60 (m, 2H), 1.18-1.34 (m, 2H), 0.80 (t, J=7.6 Hz, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ ppm −61.21 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd.for C₁₉H₂₀F₃N₂O₂, 365.1471; found 365.1476.

Example 31

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)adamantane-1-carboxamide(XJB06-049, NCGC00189460-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=7.461 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.68 (s, 1H), 10.64 (s, 1H), 8.34 (dd,J=8.3, 1.3 Hz, 1H), 8.07 (t, J=2.2 Hz, 1H), 7.95-8.04 (m, 1H), 7.85 (dd,J=7.8, 1.6 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.53 (ddd, J=8.6, 7.2, 1.7Hz, 1H), 7.41-7.50 (m, 1H), 7.17-7.26 (m, 1H), 1.90-2.10 (m, 3H),1.79-1.89 (m, 6H), 1.57-1.75 (m, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.22 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₆F₃N₂O₂,443.1941; found 443.1939.

Example 32

This example illustrates a synthesis of2-Amino-N-(furan-2-ylmethyl)benzamide (XJB06-052, NCGC00165247-02). Asolution of methyl 2-aminobenzoate (0.857 mL, 6.62 mmol) andfuran-2-ylmethanamine (1.84 mL, 19.9 mmol) in toluene (20.0 mL) wastreated at room temperature with AlMe₃ (6.62 mL, 2.0 M in toluene, 13.2mmol). The reaction mixture was stirred at 100° C. for 5 h and thenquenched with water after cooling to room temperature. The reactionmixture was concentrated in vacuo and the crude residue was purified viasilica gel chromatography using a gradient of 0-80% of EtOAc in hexanesto give 1.35 g (94%) of the title compound as a white solid. LC-MSRetention Time: t₁ (Method 1)=3.644 min.

Example 33

This example illustrates a synthesis of2-(Cyclobutanecarboxamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB06-053, NCGC00189459-01). The title compound was prepared accordingto general protocol B. LC-MS Retention Time: t₁ (Method 1)=6.412 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.61 (s, 1H), 10.22 (s, 1H), 8.15 (t,J=2.2 Hz, 1H), 8.09 (dt, J=8.1, 0.6 Hz, 1H), 7.93 (ddd, J=8.2, 1.2, 1.0Hz, 1H), 7.75 (dd, J=7.8, 1.6 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.51(ddd, J=8.5, 7.2, 1.6 Hz, 1H), 7.40-7.48 (m, 1H), 7.21 (td, J=7.6, 1.3Hz, 1H), 3.15-3.26 (m, 1H), 2.01-2.24 (m, 4H), 1.80-1.97 (m, 1H),1.64-1.80 (m, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.18 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₁₉H₁₈F₃N₂O₂, 363.1315; found 363.1317.

Example 34

This example illustrates a synthesis of2-(4-Methylcyclohexanecarboxamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB06-054, NCGC00189458-01, mixture of cis- and trans-isomers). Thetitle compound was prepared according to general protocol B. LC-MSRetention Time: t₁ (Method 1)=7.150 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.60 (s, 1H), 10.32 (s, 0.5 H), 10.27 (s, 0.5 H), 8.09-8.18 (m, 1H),8.02-8.09 (m, 1H), 7.88-7.97 (m, 1H), 7.68-7.80 (m, 1H), 7.54-7.61 (m,1H), 7.47-7.54 (m, 1H), 7.40-7.47 (m, 1H), 7.14-7.26 (m, 1H), 2.13-2.26(m, 1H), 1.73-1.89 (m, 2H), 1.66 (dd, J=13.4, 3.4 Hz, 1H), 1.13-1.60 (m,5H), 0.85-1.01 (m, 1H), 0.83 (d, J=6.7 Hz, 1.5 H), 0.80 (d, J=6.8 Hz,1.5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.21 (s, 3 F); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₂H₂₄F₃N₂O₂, 405.1784; found 405.1788.

Example 35

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide(XJB06-055, NCGC00189457-01). The title compound was prepared accordingto general protocol B. LC-MS Retention Time: t₁ (Method 1)=6.524 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.19 (s, 1H), 10.72 (s, 1H), 8.28 (dd,J=8.3, 1.3 Hz, 1H), 8.08 (t, J=2.2 Hz, 1H), 7.92-8.01 (m, 1H), 7.87 (dd,J=7.8, 1.6 Hz, 1H), 7.53-7.64 (m, 2H), 7.41-7.49 (m, 2H), 7.37 (d, J=1.8Hz, 1H), 7.27 (td, J=7.6, 1.3 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.11 (s,2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.18 (s, 3 F); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₂H₁₆F₃N₂O₄, 429.1057; found 429.1055.

Example 36

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)cyclo-heptanecarboxamide(XJB06-056, NCGC00189456-01, CID-56593317). The title compound wasprepared according to general protocol B. LC-MS Retention Time: t₁(Method 1)=7.093 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.58 (s, 1H),10.18 (s, 1H), 8.13 (s, 1H), 7.98 (dd, J=8.1, 0.9 Hz, 1H), 7.93 (d,J=8.0 Hz, 1H), 7.71 (dd, J=7.8, 1.6 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H),7.49 (ddd, J=8.4, 7.2, 1.6 Hz, 1H), 7.39-7.46 (m, 1H), 7.21 (td, J=7.6,1.2 Hz, 1H), 2.40-2.51 (m, 1H), 1.75-1.88 (m, 2H), 1.31-1.71 (m, 10H);¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.20 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₂H₂₄F₃N₂O₂, 405.1784; found 405.1794.

Example 37

This example illustrates a synthesis of2-Benzamido-N-(3-(trifluoromethyl)phenyl)benzamide (XJB06-058,NCGC00189455-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.644 min; HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₁H₁₆F₃N₂O₂, 385.1158; found 385.1163.

Example 38

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)isonicotinamide(XJB06-059, NCGC00189454-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=5.174 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.35 (s, 1H), 10.74 (d, J=0.4 Hz, 1H),8.67-8.99 (m, 2H), 8.13-8.22 (m, 1H), 8.04-8.11 (m, 1H), 7.94-8.02 (m,1H), 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.74-7.81 (m, 2H), 7.52-7.67 (m, 2H),7.44 (dt, J=7.7, 1.0 Hz, 1H), 7.34 (td, J=7.6, 1.3 Hz, 1H); ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −61.18 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₀H₁₅F₃N₃O₂, 386.1111; found 386.1123.

Example 39

This example illustrates a synthesis ofN-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide(XJB06-060, NCGC00189453-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.571 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.31 (s, 1H), 10.73 (s, 1H), 8.21 (dd,J=8.2, 1.2 Hz, 1H), 8.10 (td, J=1.8, 0.9 Hz, 1H), 7.99 (d, J=8.8 Hz,1H), 7.81-7.92 (m, 2H), 7.75 (dd, J=3.8, 1.3 Hz, 1H), 7.55-7.63 (m, 2H),7.43-7.49 (m, 1H), 7.29 (td, J=7.6, 1.2 Hz, 1H), 7.22 (dd, J=5.0, 3.8Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.16 (s, 3 F); HRMS (ESI)m/z (M+H)⁺ calcd. for C₁₉H₁₄F₃N₂O₂S, 391.0723; found 391.0731.

Example 40

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)furan-2-carboxamide(XJB06-061, NCGC00189452-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.221 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.42 (s, 1H), 10.77 (s, 1H), 8.41 (dd,J=8.4, 1.4 Hz, 1H), 8.04-8.15 (m, 1H), 7.98-8.04 (m, 1H), 7.96 (dd,J=1.9, 0.9 Hz, 1H), 7.91 (dd, J=8.0, 1.6 Hz, 1H), 7.52-7.65 (m, 2H),7.44-7.50 (m, 1H), 7.28 (td, J=7.6, 1.2 Hz, 1H), 7.24 (dd, J=3.5, 0.8Hz, 1H), 6.69 (dd, J=3.5, 1.8 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.15 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₁₉H₁₄F₃N₂O₃,375.0951; found 375.0957.

Example 41

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide(XJB06-062, NCGC00189451-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=5.342 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.27 (s, 1H), 10.74 (s, 1H), 8.95-9.12 (m,1H), 8.67-8.91 (m, 1H), 8.19-8.29 (m, 1H), 8.17 (dd, J=8.3, 1.3 Hz, 1H),8.10 (t, J=2.1 Hz, 1H), 7.92-8.02 (m, 1H), 7.86 (dd, J=7.8, 1.6 Hz, 1H),7.52-7.69 (m, 3H), 7.38-7.48 (m, 1H), 7.33 (td, J=7.6, 1.4 Hz, 1H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ ppm −61.20 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₀H₁₅F₃N₃O₂, 386.1111; found 386.1116.

Example 42

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)isoxazole-5-carboxamide(XJB06-063, NCGC00189450-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.043 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.63 (s, 1H), 10.79 (s, 1H), 8.80 (d,J=2.0 Hz, 1H), 8.23 (dd, J=8.4, 1.2 Hz, 1H), 8.08-8.15 (m, 1H), 7.99(dd, J=8.3, 1.5 Hz, 1H), 7.91 (dd, J=7.8, 1.6 Hz, 1H), 7.56-7.68 (m,2H), 7.44-7.51 (m, 1H), 7.36 (td, J=7.6, 1.4 Hz, 1H), 7.19 (d, J=2.0 Hz,1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.18 (s, 3 F); HRMS (ESI) m/z(M+H)⁺ calcd. for C₁₈H₁₃F₃N₃O₃, 376.0904; found 376.0910.

Example 43

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(2-((furan-2-ylmethyl)carbamoyl)phenyl)benzamide(XJB06-065, NCGC00189449-01). A solution of methyl2-(cyclohexanecarboxamido)benzoate (50.0 mg, 0.191 mmol) and2-amino-N-(furan-2-ylmethyl)benzamide (41.4 mg, 0.191 mmol) in toluene(2.00 mL) was treated at room temperature with AlMe₃ (0.192 mL, 2.0 M intoluene, 0.384 mmol). The reaction mixture was stirred at 100° C. forovernight and then quenched with 100 μL of water. The mixture wasconcentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified viaC₁₈ reverse phase HPLC to give the title compound as a white solid.LC-MS Retention Time: t₁ (Method 1)=6.799 min; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 12.07 (s, 1H), 10.69 (s, 1H), 9.29 (t, J=5.8 Hz, 1H), 8.41 (dd,J=8.3, 1.3 Hz, 1H), 8.22 (dd, J=8.3, 1.3 Hz, 1H), 7.80 (dd, J=8.0, 1.6Hz, 1H), 7.73 (dd, J=7.8, 1.6 Hz, 1H), 7.45-7.64 (m, 3H), 7.13-7.29 (m,J=7.9, 7.7, 7.7, 1.3 Hz, 2H), 6.36 (dd, J=3.2, 1.9 Hz, 1H), 6.22-6.33(m, 1H), 4.45 (d, J=5.5 Hz, 2H), 2.18-2.36 (m, 1H), 1.76-1.91 (m, 2H),1.64-1.76 (m, 2H), 1.50-1.64 (m, 1H), 1.05-1.44 (m, 5H); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₆H₂₈N₃O₄, 446.2074; found 446.2080.

Example 44

This example illustrates a synthesis of Methyl2-(furan-2-carboxamido)benzoate (XJB06-066, NCGC00026064-02). A solutionof methyl 2-aminobenzoate (1.71 mL, 13.2 mmol) in dichloromethane (50.0mL) and TEA (5.53 mL, 39.7 mmol) was treated at room temperature withfuran-2-carbonyl chloride (2.62 mL, 26.5 mmol). The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was quenchedwith methanol, concentrated, and purified via silica gel chromatographyusing a gradient of 0-40% of EtOAc in hexanes to give 3.00 g (92%) ofthe title compound as a white solid. LC-MS Retention Time: t₁ (Method1)=6.516 min.

Example 45

This example illustrates a synthesis ofN-(2-((2-((Furan-2-ylmethyl)carbamoyl)phenyl)carbamoyl)phenyl)furan-2-carboxamide(XJB06-067, NCGC00052938-02). A solution of2-(furan-2-carboxamido)benzoate (50.0 mg, 0.204 mmol) and2-amino-N-(furan-2-ylmethyl)benzamide (44.1 mg, 0.204 mmol) in toluene(2.00 mL) was treated at room temperature with AlMe₃ (0.204 mL, 2.0 M intoluene, 0.408 mmol). The reaction mixture was stirred at 100° C. forovernight and then quenched with 100 μL of water. The mixture wasconcentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified viaC₁₈ reverse phase HPLC to give the title compound as a white solid.LC-MS Retention Time: t₁ (Method 1)=6.103 min; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 12.33 (s, 1H), 11.87 (s, 1H), 9.32 (t, J=5.3 Hz, 1H), 8.53 (dd,J=8.4, 1.4 Hz, 1H), 8.45 (dd, J=8.3, 1.3 Hz, 1H), 7.97 (dd, J=1.8, 1.0Hz, 1H), 7.86 (dd, J=8.0, 1.6 Hz, 1H), 7.83 (dd, J=8.0, 1.6 Hz, 1H),7.55-7.67 (m, 2H), 7.53 (dd, J=2.0, 1.0 Hz, 1H), 7.27-7.35 (m, 1H),7.18-7.27 (m, 2H), 6.70 (dd, J=3.5, 1.8 Hz, 1H), 6.35 (dd, J=3.2, 1.9Hz, 1H), 6.28 (dd, J=3.1, 1.0 Hz, 1H), 4.44 (d, J=5.5 Hz, 2H); HRMS(ESI) m/z (M+H)⁺ calcd. for C₂₄H₂₀N₃O₅, 430.1397; found 430.1406.

Example 46

This example illustrates a synthesis of2-(3-(Trifluoromethyl)benzamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB06-070, NCGC00189448-01). The title compound was prepared accordingto general protocol D. LC-MS Retention Time: t₁ (Method 1)=7.060 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.28 (s, 1H), 10.72 (s, 1H), 8.13-8.32 (m,3H), 8.11 (dd, J=8.2, 1.2 Hz, 1H), 7.88-8.00 (m, 2H), 7.84 (dd, J=7.8,1.6 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.49-7.66 (m, 2H), 7.39-7.45 (m,1H), 7.33 (td, J=7.6, 1.4 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.32 (s, 6 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₅F₆N₂O₂,453.1032; found 453.1033.

Example 47

This example illustrates a synthesis of2-Acetamido-N-(3-(trifluoromethyl)phenyl)benzamide (XJB06-071,NCGC00189447-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=5.593 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.64 (s, 1H), 10.18 (br. s., 1H), 8.18 (t, J=2.2Hz, 1H), 7.97-8.04 (m, 1H), 7.92 (dt, J=8.0, 1.2 Hz, 1H), 7.71 (dd,J=7.7, 1.7 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.50 (ddd, J=8.4, 7.1, 1.7Hz, 1H), 7.41-7.47 (m, 1H), 7.21 (td, J=7.6, 1.3 Hz, 1H), 2.02 (s, 3H);¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.18 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₁₆H₁₄F₃N₂O₂, 323.1002; found 323.1010.

Example 48

This example illustrates a synthesis of2-Acetamido-N-(3-(trifluoromethyl)phenyl)benzamide (XJB06-072,NCGC00189446-01). The title compound was prepared according to generalprotocol D. LC-MS Retention Time: t₁ (Method 1)=7.415 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.25 (s, 1H), 10.71 (s, 1H), 8.39-8.57 (m, 2H),8.35 (s, 1H), 8.19 (s, 1H), 7.92-8.00 (m, 1H), 7.84-7.92 (m, 1H), 7.81(dd, J=7.7, 1.7 Hz, 1H), 7.58-7.68 (m, 1H), 7.53 (t, J=7.9 Hz, 1H),7.22-7.47 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.42 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₁₄F₉N₂O₂, 521.0906; found 521.0905.

Example 49

This example illustrates a synthesis of2-(2-Phenylacetamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB06-074,NCGC00189445-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.443 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.61 (s, 1H), 10.30 (s, 1H), 8.17 (t, J=2.1 Hz,1H), 8.00-8.07 (m, 1H), 7.83-7.91 (m, 1H), 7.71 (dd, J=7.8, 1.6 Hz, 1H),7.57 (t, J=7.9 Hz, 1H), 7.50 (ddd, J=8.5, 7.2, 1.6 Hz, 1H), 7.41-7.47(m, 1H), 7.11-7.34 (m, 6H), 3.66 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δppm −61.15 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₈F₃N₂O₂,399.1315; found 399.1312.

Example 50

This example illustrates a synthesis of2-(Cyclopropanecarboxamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB06-081, NCGC00189444-01). The title compound was prepared accordingto general protocol B. LC-MS Retention Time: t₁ (Method 1)=6.131 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.61 (s, 1H), 10.46 (s, 1H), 8.17 (s, 1H),7.95-8.08 (m, 1H), 7.91 (dd, J=7.9, 1.3 Hz, 1H), 7.71 (dd, J=7.9, 1.5Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.46-7.53 (m, 1H), 7.40-7.46 (m, 1H),7.20 (tt, J=7.6, 0.8 Hz, 1H), 1.61-1.81 (m, 1H), 0.65-0.79 (m, 4H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ ppm −61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₁₈H₁₆F₃N₂O₂, 349.1158; found 349.1160.

Example 51

This example illustrates a synthesis ofN-(3-(tert-Butyl)phenyl)-2-(cyclohexanecarboxamido)benzamide (XJB07-026,NCGC00238733-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=7.324 min; HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₄H₃₁N₂O₂, 379.2380; found 379.2387.

Example 52

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(2,3-dihydro-1H-inden-5-yl)benzamide(XJB07-028, NCGC00238732-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=7.053 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H), 10.27 (s, 1H), 8.26 (d,J=8.2 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.55 (s, 1H), 7.42-7.51 (m, 1H),7.31-7.41 (m, 1H), 7.08-7.23 (m, 2H), 2.74-2.90 (m, 4H), 2.17-2.32 (m,1H), 1.92-2.08 (m, J=7.8, 7.5, 7.4, 7.4 Hz, 2H), 1.76-1.89 (m, 2H),1.63-1.76 (m, 2H), 1.52-1.63 (m, 1H), 1.05-1.46 (m, 5H); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₃H₂₇N₂O₂, 363.2067; found 363.2075.

Example 53

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(1H-indol-5-yl)benzamide (XJB07-031,NCGC00238734-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=5.982 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.04 (br. s., 1H), 10.87 (s, 1H), 10.26 (s, 1H),8.34 (d, J=8.4 Hz, 1H), 7.65-8.00 (m, 2H), 7.44-7.53 (m, 1H), 7.24-7.41(m, 3H), 7.16 (t, J=7.6 Hz, 1H), 6.31-6.45 (m, 1H), 2.17-2.31 (m, 1H),1.77-1.92 (m, 2H), 1.68 (ddd, J=12.5, 3.4, 3.2 Hz, 2H), 1.51-1.62 (m,1H), 1.01-1.44 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₄N₃O₂,362.1863; found 362.1867.

Example 54

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-iodophenyl)benzamide (XJB07-032,NCGC00238735-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=7.076 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.39 (s, 1H), 10.32 (s, 1H), 8.05-8.20 (m, 2H),7.68-7.76 (m, 1H), 7.66 (ddd, J=8.2, 1.1, 0.9 Hz, 1H), 7.39-7.55 (m,2H), 7.06-7.27 (m, 2H), 2.11-2.33 (m, 1H), 1.79 (dd, J=12.7, 2.2 Hz,2H), 1.63-1.73 (m, 2H), 1.49-1.63 (m, 1H), 1.05-1.44 (m, 5H); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₀H₂₂IN₂O₂, 449.0720; found 449.0720.

Example 55

This example illustrates a synthesis ofN-(3-Chlorophenyl)-2-(cyclohexanecarboxamido)benzamide (XJB07-033,NCGC00238736-01, CID-56593336). The title compound was preparedaccording to general protocol A. LC-MS Retention Time: t₁ (Method1)=6.898 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.48 (s, 1H), 10.31 (s,1H), 8.11 (d, J=7.8 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 7.71 (dd, J=7.7,1.3 Hz, 1H), 7.59 (dd, J=8.0, 1.8 Hz, 1H), 7.43-7.54 (m, 1H), 7.35 (t,J=8.1 Hz, 1H), 7.06-7.24 (m, 2H), 2.26 (tt J=11.3, 3.6 Hz, 1H), 1.79 (d,J=14.1 Hz, 2H), 1.68 (ddd, J=12.7, 3.0, 2.7 Hz, 2H), 1.52-1.62 (m, 1H),1.03-1.41 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂ClN₂O₂,357.1364; found 357.1366.

Example 56

This example illustrates a synthesis ofN-([1,1′-Biphenyl]-3-yl)-2-(cyclohexanecarboxamido)benzamide (XJB07-034,NCGC00238737-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=7.181 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.49 (s, 1H), 10.44 (s, 1H), 8.19 (ddd, J=8.2, 0.8,0.6 Hz, 1H), 7.96 (t, J=2.0 Hz, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.70(dt, J=7.6, 1.9 Hz, 1H), 7.56-7.66 (m, 2H), 7.31-7.55 (m, 6H), 7.15-7.23(m, 1H), 2.19-2.32 (m, 1H), 1.76-1.87 (m, 2H), 1.62-1.74 (m, 2H),1.52-1.62 (m, 1H), 1.04-1.45 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₆H₂₇N₂O₂, 399.2067; found 399.2071.

Example 57

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-ethynylphenyl)benzamide (XJB07-035,NCGC00238738-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.586 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.42 (s, 1H), 10.38 (s, 1H), 8.15 (d, J=8.2 Hz,1H), 7.84 (s, 1H), 7.71-7.78 (m, 1H), 7.62-7.71 (m, 1H), 7.44-7.53 (m,1H), 7.34 (t, J=8.0 Hz, 1H), 7.14-7.24 (m, 2H), 4.17 (s, 1H), 2.08-2.35(m, 1H), 1.74-1.89 (m, 2H), 1.62-1.74 (m, 2H), 1.53-1.62 (m, 1H),1.00-1.43 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₃N₂O₂,347.1754; found 347.1757.

Example 58

This example illustrates a synthesis ofN-(4-(tert-Butyl)phenyl)-2-(cyclohexanecarboxamido)benzamide (XJB07-037,NCGC00238739-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=7.389 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.63 (s, 1H), 10.33 (s, 1H), 8.26 (d, J=8.2 Hz,1H), 7.76 (dt, J=7.9, 1.0 Hz, 1H), 7.52-7.61 (m, 2H), 7.43-7.52 (m, 1H),7.29-7.42 (m, 2H), 7.17 (tt, J=7.6, 1.0 Hz, 1H), 2.16-2.29 (m, 1H),1.77-1.89 (m, 2H), 1.64-1.77 (m, 2H), 1.49-1.64 (m, 1H), 1.25 (s, 9H),1.01-1.44 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₄H₃₁N₂O₂,379.2380; found 379.2391.

Example 59

This example illustrates a synthesis ofN-(Benzo[d][1,3]dioxol-5-yl)-2-(cyclohexanecarboxamido)benzamide(XJB07-039, NCGC00238740-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.279 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.57 (s, 1H), 10.28 (s, 1H), 8.23 (d,J=8.6 Hz, 1H), 7.73 (dd, J=7.9, 1.7 Hz, 1H), 7.44-7.62 (m, 1H),7.26-7.35 (m, 1H), 7.13-7.21 (m, 1H), 7.08 (dd, J=8.4, 2.0 Hz, 1H), 6.88(d, J=8.4 Hz, 1H), 5.98 (s, 2H), 2.25 (tt, J=11.3, 3.6 Hz, 1H),1.75-1.90 (m, 2H), 1.64-1.75 (m, 2H), 1.50-1.64 (m, 1H), 1.01-1.43 (m,5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₃N₂O₄, 367.1652; found367.1657.

Example 60

This example illustrates a synthesis of2-(3-Nitrobenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-047,NCGC00238741-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.687 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.32 (s, 1H), 10.73 (s, 1H), 8.68 (t, J=2.1 Hz,1H), 8.36-8.48 (m, 1H), 8.29 (dt, J=7.8, 1.5 Hz, 1H), 8.12 (s, 1H),7.99-8.10 (m, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.76-7.88 (m, 2H), 7.58-7.66(m, J=7.6, 7.6, 1.2, 0.8 Hz, 1H), 7.50-7.58 (m, 1H), 7.38-7.45 (m, 1H),7.29-7.38 (m, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.34 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₅F₃N₃O₄, 430.1009; found 430.1012.

Example 61

This example illustrates a synthesis of2-(3-Cyanobenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-048,NCGC00238743-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.508 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.16 (s, 1H), 10.71 (s, 1H), 8.27 (t, J=1.8 Hz,1H), 8.15 (dt, J=7.9, 1.6 Hz, 1H), 8.01-8.12 (m, 3H), 7.88-7.96 (m, 1H),7.79-7.87 (m, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.51-7.65 (m, 2H), 7.42 (d,J=7.6 Hz, 1H), 7.32 (td, J=7.7, 0.8 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆)δ ppm −61.33 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₅F₃N₃O₂,410.1111; found 410.1120.

Example 62

This example illustrates a synthesis of2-Bromo-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB07-050, NCGC00238742-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.641 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₅BrF₃N₂O₂, 463.0264; found463.0264.

Example 63

This example illustrates a synthesis of2-(4-Chlorobenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-051,NCGC00238744-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=7.132 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.26 (s, 1H), 10.72 (s, 1H), 8.21 (d, J=8.2 Hz,1H), 8.06 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.82-7.93 (m, 3H), 7.52-7.66(m, 4H), 7.44 (d, J=7.8 Hz, 1H), 7.30 (t, J=7.4 Hz, 1H); ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₁H₁₅ClF₃N₂O₂, 419.0769; found 419.0775.

Example 64

This example illustrates a synthesis of2-(4-Methylbenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-052,NCGC00238745-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.967 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.31 (s, 1H), 10.73 (s, 1H), 8.33 (d, J=8.4 Hz,1H), 8.08 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.88 (dd, J=7.6, 1.6 Hz, 1H),7.78 (d, J=8.2 Hz, 2H), 7.53-7.64 (m, 2H), 7.45 (ddd, J=7.7, 1.8, 0.9Hz, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.27 (td, J=7.6, 1.2 Hz, 1H), 2.34 (s,3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.28 (s, 3 F); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₂H₁₈F₃N₂O₂, 399.1315; found 399.1321.

Example 65

This example illustrates a synthesis of2-(4-(Trifluoromethyl)benzamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB07-054, NCGC00238746-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=7.128 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.33 (d, J=0.4 Hz, 1H), 10.73 (s, 1H),8.19 (d, J=8.2 Hz, 1H), 8.01-8.11 (m, 3H), 7.97 (d, J=8.4 Hz, 1H), 7.90(d, J=8.6 Hz, 2H), 7.82-7.88 (m, 1H), 7.51-7.64 (m, 2H), 7.40-7.45 (m,1H), 7.32 (t, J=7.4 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.30 (s,3 F), −61.45 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₅F₆N₂O₂,453.1032; found 453.1034.

Example 66

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-3-carboxamide(XJB07-055, NCGC00238747-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=7.398 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.40 (s, 1H), 10.76 (s, 1H), 8.25-8.35 (m,1H), 8.10-8.22 (m, 2H), 7.99 (d, J=8.2 Hz, 1H), 7.81-7.94 (m, 3H),7.67-7.75 (m, 2H), 7.54-7.66 (m, 3H), 7.43-7.51 (m, 3H), 7.37-7.43 (m,1H), 7.32 (td, J=7.6, 1.3 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₀F₃N₂O₂,461.1471; found 461.1478.

Example 67

This example illustrates a synthesis of2-(3-Methylbenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-056,NCGC00238759-02). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.975 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.27 (s, 1H), 10.75 (s, 1H), 8.30 (dd, J=8.3, 1.3Hz, 1H), 8.14 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.88 (dd, J=7.8, 1.6 Hz,1H), 7.71 (t, J=1.7 Hz, 1H), 7.64-7.69 (m, 1H), 7.54-7.64 (m, 2H),7.43-7.48 (m, 1H), 7.37-7.43 (m, 2H), 7.30 (td, J=7.6, 1.3 Hz, 1H), 2.36(s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.31 (s, 3 F); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₂H₁₈F₃N₂O₂, 399.1315; found 399.1323.

Example 68

This example illustrates a synthesis of2-(4-Methoxybenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB07-057, NCGC00238760-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.679 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.31 (s, 1H), 10.75 (s, 1H), 8.36 (dd,J=8.3, 1.3 Hz, 1H), 8.08 (t, J=2.2 Hz, 1H), 8.01 (ddd, J=8.2, 1.2, 1.0Hz, 1H), 7.78-7.92 (m, 3H), 7.54-7.64 (m, 2H), 7.42-7.49 (m, 1H), 7.27(td, J=7.6, 1.2 Hz, 1H), 7.00-7.12 (m, 2H), 3.81 (s, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −61.25 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₂H₁₈F₃N₂O₃, 415.1264; found 415.1272.

Example 69

This example illustrates a synthesis of2-Methyl-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB07-058, NCGC00238761-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.769 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.74 (s, 1H), 10.70 (s, 1H), 8.08-8.19 (m,2H), 7.95 (dt, J=8.2, 1.2 Hz, 1H), 7.79 (dd, J=7.8, 1.8 Hz, 1H),7.48-7.65 (m, 3H), 7.33-7.47 (m, 2H), 7.22-7.33 (m, 3H), 2.37 (s, 3H);¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.30 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₂H₁₈F₃N₂O₂, 399.1315; found 399.1324.

Example 70

This example illustrates a synthesis of2-(Trifluoromethyl)-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB07-059, NCGC00238762-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.708 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.83 (s, 1H), 10.71 (s, 1H), 8.13 (s, 1H),8.00 (d, J=8.2 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.64-7.87 (m, 5H),7.49-7.63 (m, 2H), 7.42 (dt, J=7.8, 1.0 Hz, 1H), 7.33 (td, J=7.6, 1.4Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −57.86 (s, 3 F), −61.31 (s, 3F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₅F₆N₂O₂, 453.1032; found453.1027.

Example 71

This example illustrates a synthesis of2-(3-Methoxybenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB07-060, NCGC00238763-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.778 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.33 (s, 1H), 10.75 (s, 1H), 8.32 (dd,J=8.3, 1.3 Hz, 1H), 8.14 (t, J=2.1 Hz, 1H), 7.98 (dt, J=8.1, 1.2 Hz,1H), 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.52-7.66 (m, 2H), 7.39-7.52 (m, 4H),7.30 (td, J=7.6, 1.4 Hz, 1H), 7.13-7.25 (m, 1H), 3.80 (s, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ ppm −61.31 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₂H₁₈F₃N₂O₃, 415.1264; found 415.1270.

Example 72

This example illustrates a synthesis of2-(3-Chlorobenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-062,NCGC00238764-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=7.105 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.20 (s, 1H), 10.73 (s, 1H), 8.15 (dd, J=8.2, 1.4Hz, 1H), 8.13 (t, J=2.1 Hz, 1H), 7.92-7.99 (m, 1H), 7.90 (t, J=2.0 Hz,1H), 7.76-7.89 (m, 2H), 7.64-7.69 (m, 1H), 7.53-7.64 (m, 3H), 7.40-7.47(m, 1H), 7.33 (td, J=7.6, 1.2 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.30 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₅ClF₃N₂O₂,419.0769; found 419.0772.

Example 73

This example illustrates a synthesis of2-Methoxy-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB07-063, NCGC00238748-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.734 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.54 (s, 1H), 10.84 (s, 1H), 8.52-8.63 (m,1H), 8.32 (t, J=2.2 Hz, 1H), 7.94-8.06 (m, 2H), 7.79 (dd, J=7.7, 1.7 Hz,1H), 7.51-7.68 (m, 3H), 7.43-7.51 (m, 1H), 7.24-7.30 (m, 1H), 7.17-7.23(m, 1H), 6.99-7.13 (m, 1H), 3.97 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δppm −61.40 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₈F₃N₂O₃,415.1264; found 415.1266.

Example 74

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)-1-naphthamide(XJB07-064, NCGC00238749-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.952 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.94 (s, 1H), 10.74 (s, 1H), 8.26-8.32 (m,1H), 8.16 (t, J=2.2 Hz, 1H), 8.02-8.11 (m, 2H), 7.91-8.01 (m, 2H), 7.81(dd, J=3.2, 1.5 Hz, 1H), 7.79 (dd, J=3.9, 1.6 Hz, 1H), 7.44-7.67 (m,5H), 7.38-7.43 (m, 1H), 7.34 (td, J=7.6, 1.3 Hz, 1H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₅H₁₈F₃N₂O₂, 435.1315; found 435.1318.

Example 75

This example illustrates a synthesis of2-(3-Bromobenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-065,NCGC00238750-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=7.174 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.19 (s, 1H), 10.73 (s, 1H), 8.09-8.24 (m, 2H),8.04 (t, J=1.8 Hz, 1H), 7.96 (dt, J=8.2, 1.2 Hz, 1H), 7.82-7.91 (m, 2H),7.79 (ddd, J=8.0, 2.1, 1.1 Hz, 1H), 7.54-7.65 (m, 2H), 7.50 (t, J=7.8Hz, 1H), 7.44 (dt, J=7.8, 0.9 Hz, 1H), 7.32 (td, J=7.6, 1.3 Hz, 1H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ ppm −61.29 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₁H₁₅BrF₃N₂O₂, 463.0264; found 463.0271.

Example 76

This example illustrates a synthesis of2-(4-Cyanobenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-066,NCGC00238751-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.522 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.32 (s, 1H), 10.74 (s, 1H), 8.18 (dd, J=8.2, 1.2Hz, 1H), 8.08 (t, J=2.2 Hz, 1H), 8.00-8.06 (m, 4H), 7.94-7.99 (m, 1H),7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.54-7.66 (m, 2H), 7.40-7.50 (m, 1H), 7.34(td, J=7.6, 1.4 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.27 (s, 3F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₅F₃N₃O₂, 410.1111; found410.1119.

Example 77

This example illustrates a synthesis of2-(4-Nitrobenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-067,NCGC00238752-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.711 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.36 (s, 1H), 10.75 (s, 1H), 8.33-8.41 (m, 2H),8.16 (dd, J=8.2, 1.2 Hz, 1H), 8.05-8.14 (m, 3H), 7.93-8.01 (m, 1H),7.83-7.92 (m, 1H), 7.63 (ddd, J=8.4, 7.3, 1.6 Hz, 1H), 7.58 (t, J=8.0Hz, 1H), 7.45 (dt, J=7.8, 0.9 Hz, 1H), 7.35 (td, J=7.6, 1.2 Hz, 1H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ ppm −61.27 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₁H₁₅F₃N₃O₄, 430.1009; found 430.1008.

Example 78

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)-2-naphthamide(XJB07-069, NCGC00238753-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=7.197 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₁₈F₃N₂O₂, 435.1315; found 435.1314.

Example 79

This example illustrates a synthesis of2-(4-Bromobenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-073,NCGC00238754-01). A solution of2-amino-N-(3-(trifluoromethyl)phenyl)benzamide (50.0 mg, 0.178 mmol) indichloromethane (2.00 mL) and TEA (0.075 mL, 0.535 mmol) was treated atroom temperature with 4-bromobenzoyl bromide (70.6 mg, 0.268 mmol). Thereaction mixture was stirred at room temperature for overnight. Themixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered andpurified via C₁₈ reverse phase HPLC to give the final product. LC-MSRetention Time: t₁ (Method 1)=7.158 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.28 (s, 1H), 10.74 (s, 1H), 8.23 (dd, J=8.2, 1.2 Hz, 1H), 8.08 (t,J=2.2 Hz, 1H), 7.92-8.02 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.79-7.85 (m, 2H), 7.72-7.78 (m, 2H), 7.55-7.64 (m, 2H), 7.42-7.50 (m,1H), 7.27-7.36 (m, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.26 (s, 3F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₅BrF₃N₂O₂, 463.0264; found463.0268.

Example 80

This example illustrates a synthesis of2-(3-(Methylsulfonyl)benzamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB07-075, NCGC00238755-01). The title compound was prepared accordingto general protocol D. LC-MS Retention Time: t₁ (Method 1)=6.025 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.30 (s, 1H), 10.74 (s, 1H), 8.42 (t,J=1.9 Hz, 1H), 8.20 (ddd, J=7.9, 1.5, 1.4 Hz, 1H), 8.08-8.17 (m, 3H),7.97 (d, J=8.2 Hz, 1H), 7.77-7.89 (m, 2H), 7.62 (ddd, J=8.4, 7.2, 1.6Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.44 (dd, J=6.8, 1.2 Hz, 1H), 7.35 (td,J=7.6, 1.2 Hz, 1H), 3.25 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₈F₃N₂O₄S,463.0934; found 463.0939.

Example 81

This example illustrates a synthesis of2-(4-Acetylbenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-076,NCGC00238756-01). The title compound was prepared according to generalprotocol D. LC-MS Retention Time: t₁ (Method 1)=6.474 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.38 (s, 1H), 10.76 (s, 1H), 8.21-8.30 (m, 1H),8.04-8.12 (m, 3H), 7.94-8.03 (m, 3H), 7.89 (dd, J=7.8, 1.6 Hz, 1H),7.54-7.68 (m, 2H), 7.41-7.52 (m, 1H), 7.33 (td, J=7.6, 1.2 Hz, 1H), 2.62(s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.26 (s, 3 F); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₃H₁₈F₃N₂O₃, 427.1264; found 427.1267.

Example 82

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-isopropylphenyl)benzamide (XJB07-080,NCGC00238757-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=7.166 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.52 (s, 1H), 10.30 (s, 1H), 8.21 (dd, J=8.4, 1.4Hz, 1H), 7.77 (dd, J=7.8, 1.6 Hz, 1H), 7.44-7.58 (m, 3H), 7.26 (t, J=7.8Hz, 1H), 7.19 (td, J=7.6, 1.2 Hz, 1H), 7.00 (dt, J=7.7, 1.5 Hz, 1H),2.86 (quin, J=6.8 Hz, 1H), 2.20-2.36 (m, 1H), 1.76-1.90 (m, 2H),1.65-1.76 (m, 2H), 1.55-1.65 (m, 1H), 1.20 (d, J=4.0 Hz, 6H), 1.08-1.44(m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₉N₂O₂, 365.2239; found365.2239.

Example 83

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-((5-methylfuran-2-yl)methyl)benzamide(XJB07-081, NCGC00238758-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.284 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.26 (s, 1H), 9.16 (t, J=5.5 Hz, 1H), 8.40(dd, J=8.4, 1.2 Hz, 1H), 7.72 (dd, J=7.8, 1.6 Hz, 1H), 7.42-7.48 (m,1H), 7.10 (ddd, J=8.0, 7.2, 1.2 Hz, 1H), 6.15 (d, J=2.9 Hz, 1H),5.96-6.00 (m, 1H), 4.39 (d, J=5.7 Hz, 2H), 2.21 (d, J=0.8 Hz, 3H),2.18-2.28 (m, 1H), 1.78-1.94 (m, 2H), 1.66-1.78 (m, 2H), 1.55-1.66 (m,1H), 1.07-1.47 (m, 5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₅N₂O₃,341.1860; found 341.1869.

Example 84

This example illustrates a synthesis of2-(3-Methylbenzamido)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB07-093,NCGC00238759-01). The title compound was prepared according to generalprotocol C. LC-MS Retention Time: t₁ (Method 1)=6.938 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.26 (s, 1H), 10.74 (s, 1H), 8.29 (dd, J=8.3, 0.9Hz, 1H), 8.13 (s, 1H), 7.94-7.99 (m, 1H), 7.87 (ddd, J=7.8, 1.1, 0.9 Hz,1H), 7.70 (s, 1H), 7.63-7.69 (m, 1H), 7.54-7.63 (m, 2H), 7.36-7.49 (m,3H), 7.20-7.32 (m, 1H), 2.35 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.31 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₈F₃N₂O₂,399.1315; found 399.1319.

Example 85

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-3-carboxamide(XJB07-094, NCGC00238747-02). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=7.389 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.39 (s, 1H), 10.75 (s, 1H), 8.28 (dt,J=8.3, 0.7 Hz, 1H), 8.13-8.19 (m, 2H), 7.97-8.01 (m, 1H), 7.82-7.92 (m,3H), 7.67-7.79 (m, 2H), 7.53-7.66 (m, 3H), 7.36-7.53 (m, 4H), 7.31 (tt,J=7.7, 0.7 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.29 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₀F₃N₂O₂, 461.1471; found 461.1476.

Example 86

This example illustrates a synthesis of2-Bromo-N-(3-(trifluoromethyl)phenyl)benzamide (XJB09-014). A solutionof 3-(trifluoromethyl)aniline (0.850 mL, 6.83 mmol) in dichloromethane(15.0 mL) and triethylamine (2.86 mL, 20.5 mmol) was treated at 0° C.with 2-bromobenzoyl chloride (0.893 mL, 6.83 mmol) and stirred at roomtemperature for 3 h. The reaction mixture was diluted withdichloromethane and washed with Na₂CO₃ solution. The organic layer wasseparated, dried, and concentrated to give 2.30 g (98%) of the titlecompound as a white foam which was used directly for the next reactionwithout further purification.

Example 87

This example illustrates a synthesis ofN-(3-(Trifluoromethyl)phenyl)-[1,1′-biphenyl]-2-carboxamide (XJB09-016,NCGC00244471-01). The title compound was prepared according to generalprotocol E. LC-MS Retention Time: t₁ (Method 1)=6.365 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.54 (s, 1H), 7.97 (t, J=2.1 Hz, 1H), 7.64-7.73 (m,1H), 7.55-7.64 (m, 2H), 7.44-7.54 (m, 3H), 7.32-7.44 (m, 5H), 7.25-7.32(m, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.34 (s, 3 F); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₀H₁₅F₃NO, 342.1100; found 342.1110.

Example 88

This example illustrates a synthesis of2′-(Benzyloxy)-N-(3-(trifluoromethyl)phenyl)-[1,1′-biphenyl]-2-carboxamide(XJB09-019, NCGC00244472-01). The title compound was prepared accordingto general protocol E. LC-MS Retention Time: t₁ (Method 1)=6.997 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₁F₃NO₂, 448.1519; found 448.1524.

Example 89

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)benzamide(XJB09-023, NCGC00244469-01). A mixture ofN-(3-bromophenyl)-2-(cyclohexanecarboxamido)benzamide (50.0 mg, 0.125mmol), 3-(trifluoromethyl)phenylboronic acid (35.5 mg, 0.187 mmol) andPd(PPh₃)₄ (7.2 mg, 6.23 μmol) in DMF (1.50 mL) and 2.0 N Na₂CO₃ (0.50mL) aqueous solution was heated in W at 100° C. for 30 min. The reactionwas cooled to room temperature, added a small portion of Si-THIOL to getrid of Palladium. The mixture was filtered and purified via C₁₈ reversephase HPLC to give the final product. LC-MS Retention Time: t₁ (Method1)=7.438 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (br. s., 1H), 10.49(s, 1H), 8.14-8.24 (m, 1H), 8.01-8.08 (m, 1H), 7.94-8.01 (m, 1H), 7.91(s, 1H), 7.78-7.84 (m, 2H), 7.70-7.77 (m, 2H), 7.41-7.56 (m, 3H), 7.22(td, J=7.6, 1.3 Hz, 1H), 2.21-2.35 (m, 1H), 1.83 (d, J=15.8 Hz, 2H),1.64-1.74 (m, 2H), 1.52-1.63 (m, 1H), 1.08-1.46 (m, 5H); ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −61.11 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₇H₂₆F₃N₂O₂, 467.1941; found 467.1943.

Example 90

This example illustrates a synthesis of2-Iodo-N-(3-(trifluoromethyl)phenyl)benzamide (XJB09-026). A solution of3-(trifluoromethyl)aniline (0.467 mL, 3.75 mmol) in dichloromethane(15.0 mL) and triethylamine (1.57 mL, 11.3 mmol) was treated at 0° C.with 2-iodobenzoyl chloride (1.00 g, 3.75 mmol) and stirred at roomtemperature for 3 h. The reaction mixture was diluted withdichloromethane and washed with Na₂CO₃ solution. The organic layer wasseparated, dried, and concentrated to give 1.40 g (95%) of the titlecompound as a white foam which was used directly for the next reactionwithout further purification.

Example 91

This example illustrates a synthesis of2-(Benzylamino)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB09-027,NCGC00244464-01). The title compound was prepared according to generalprotocol F. LC-MS Retention Time: t₁ (Method 1)=7.001 min; HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₁H₁₈F₃NO₂, 371.1366; found 371.1374.

Example 92

This example illustrates a synthesis of2-((2-Methoxybenzyl)amino)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB09-028, NCGC00244511-01). The title compound was prepared accordingto general protocol F. LC-MS Retention Time: t₁ (Method 1)=6.914 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.36 (s, 1H), 8.18 (t, J=2.1 Hz, 1H),7.87-8.01 (m, 1H), 7.65-7.80 (m, 2H), 7.49-7.61 (m, 1H), 7.38-7.45 (m,1H), 7.16-7.31 (m, 3H), 6.95-7.03 (m, 1H), 6.83-6.90 (m, 1H), 6.57-6.67(m, 2H), 4.35 (d, J=5.9 Hz, 2H), 3.81 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −61.25 (s, 3 F).

Example 93

This example illustrates a synthesis of2-(Phenylamino)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB09-029,NCGC00244510-01). The title compound was prepared according to generalprotocol F. LC-MS Retention Time: t₁ (Method 1)=6.999 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.59 (s, 1H), 8.99 (s, 1H), 8.18 (t, J=2.2 Hz, 1H),7.89-7.99 (m, 1H), 7.76 (dd, J=7.8, 1.6 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H),7.34-7.47 (m, 2H), 7.20-7.33 (m, 3H), 7.11-7.20 (m, 2H), 6.82-7.02 (m,2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.26 (s, 3 F); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₀H₁₆F₃N₂O, 357.1209; found 357.1216.

Example 94

This example illustrates a synthesis of2-((2-Methoxyphenyl)amino)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB09-030, NCGC00244488-01). The title compound was prepared accordingto general protocol F. LC-MS Retention Time: t₁ (Method 1)=6.918 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.59 (s, 1H), 9.02 (s, 1H), 8.13 (t, J=2.2Hz, 1H), 7.94-8.03 (m, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.53-7.65 (m,1H), 7.42-7.49 (m, 1H), 7.35-7.42 (m, 1H), 7.24-7.34 (m, 2H), 7.01-7.08(m, 1H), 6.82-7.01 (m, 3H), 3.82 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δppm −61.23 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₈F₃N₂O₂,387.1315; found 387.1322.

Example 95

This example illustrates a synthesis of2-(Phenethylamino)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB09-031,NCGC00244489-01). The title compound was prepared according to generalprotocol F. LC-MS Retention Time: t₁ (Method 1)=7.119 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.32 (s, 1H), 8.16 (t, J=2.2 Hz, 1H), 7.85-7.98 (m,1H), 7.70 (dd, J=7.9, 1.7 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.47 (t,J=5.5 Hz, 1H), 7.39-7.44 (m, 1H), 7.35 (ddd, J=8.5, 7.0, 1.6 Hz, 1H),7.23-7.31 (m, 4H), 7.12-7.22 (m, 1H), 6.76-6.87 (m, 1H), 6.64 (ddd,J=7.9, 7.0, 1.1 Hz, 1H), 3.33-3.46 (m, 2H), 2.87 (t, J=7.3 Hz, 2H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ ppm −61.25 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₂H₂₀F₃N₂O, 385.1522; found 385.1533.

Example 96

This example illustrates a synthesis of2-((2-Methoxyethyl)amino)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB09-032, NCGC00244512-01). The title compound was prepared accordingto general protocol F. LC-MS Retention Time: t₁ (Method 1)=6.254 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.33 (s, 1H), 8.14 (t, J=2.2 Hz, 1H),7.88-8.05 (m, 1H), 7.70 (dd, J=7.8, 1.6 Hz, 1H), 7.54-7.63 (m, 1H),7.44-7.52 (m, 1H), 7.37-7.44 (m, 1H), 7.34 (ddd, J=8.6, 7.0, 1.7 Hz,1H), 6.72-6.84 (m, 1H), 6.65 (ddd, J=8.0, 7.1, 1.2 Hz, 1H), 3.53 (t,J=5.5 Hz, 2H), 3.28 (s, 3H), 3.24-3.33 (m, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −61.23 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₁₇H₁₈F₃N₂O₂, 339.1315; found 339.1326.

Example 97

This example illustrates a synthesis of2-((Cyclohexylmethyl)amino)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB09-033, NCGC00244473-01). The title compound was prepared accordingto general protocol F. LC-MS Retention Time: t₁ (Method 1)=7.597 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.31 (s, 1H), 8.11 (t, J=2.2 Hz, 1H),7.92-8.00 (m, 1H), 7.70 (dd, J=8.0, 1.6 Hz, 1H), 7.49-7.61 (m, 2H),7.39-7.45 (m, 1H), 7.32 (ddd, J=8.6, 7.0, 1.6 Hz, 1H), 6.69-6.76 (m,1H), 6.61 (ddd, J=8.0, 7.1, 1.2 Hz, 1H), 2.92-3.06 (m, 2H), 1.72-1.83(m, 2H), 1.65-1.72 (m, 2H), 1.49-1.65 (m, 2H), 1.04-1.30 (m, 3H),0.88-1.05 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.21 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₄F₃N₂O, 377.1835; found 377.1843.

Example 98

This example illustrates a synthesis ofN-(3-(Trifluoromethyl)phenyl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide(XJB09-034, NCGC00244513-01). The title compound was prepared accordingto general protocol F. LC-MS Retention Time: t₁ (Method 1)=7.252 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₅F₆N₂O, 425.1083; found 425.1092.

Example 99

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-(methylthio)phenyl)benzamide (XJB09-035,NCGC00244465-02). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.687 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.44 (s, 1H), 10.37 (s, 1H), 8.18 (d, J=8.2 Hz,1H), 7.75 (dd, J=7.8, 1.6 Hz, 1H), 7.63 (t, J=2.1 Hz, 1H), 7.44-7.55 (m,2H), 7.29 (t, J=7.9 Hz, 1H), 7.20 (td, J=7.6, 1.3 Hz, 1H), 7.01 (ddd,J=7.8, 2.0, 1.0 Hz, 1H), 2.46 (s, 3H), 2.19-2.35 (m, 1H), 1.76-1.90 (m,2H), 1.65-1.76 (m, 2H), 1.52-1.65 (m, 1H), 1.03-1.47 (m, 5H); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₁H₂₅N₂O₂S, 369.1631; found 369.1625.

Example 100

This example illustrates a synthesis of2-((3-(Trifluoromethyl)benzyl)amino)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB09-037, NCGC00244514-01). The title compound was prepared accordingto general protocol F. LC-MS Retention Time: t₁ (Method 1)=7.370 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₇F₆N₂O, 439.1240; found 439.1247.

Example 101

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-(piperidin-1-yl)phenyl)benzamide(XJB09-040, NCGC00244515-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=4.605 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₃₂N₃O₂, 406.2489; found 406.2501.

Example 102

This example illustrates a synthesis of2-Chloro-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB09-047, NCGC00244490-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.765 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.83 (s, 1H), 10.70 (s, 1H), 8.01-8.22 (m,2H), 7.89-8.00 (m, 1H), 7.69-7.85 (m, 1H), 7.38-7.67 (m, 7H), 7.33 (td,J=7.6, 1.4 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.28 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₅ClF₃N₂O₂, 419.0769; found419.0769.

Example 103

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-((trifluoromethyl)thio)phenyl)benzamide(XJB09-048, NCGC00244491-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=7.349 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₂F₃N₂O₂S, 423.1349; found423.1360.

Example 104

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-(thiophen-2-yl)phenyl)benzamide(XJB09-050, NCGC00244466-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=7.234 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.46 (br. s., 1H), 10.45 (br. s., 1H),8.11-8.25 (m, 1H), 7.92-8.02 (m, 1H), 7.75-7.83 (m, 1H), 7.62-7.71 (m,1H), 7.55 (dd, J=5.1, 1.2 Hz, 1H), 7.48-7.54 (m, 1H), 7.34-7.48 (m, 3H),7.17-7.26 (m, 1H), 7.14 (dd, J=5.0, 3.6 Hz, 1H), 2.19-2.31 (m, 1H),1.78-1.89 (m, 2H), 1.65-1.76 (m, 2H), 1.53-1.64 (m, 1H), 1.08-1.47 (m,5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₄H₂₅N₂O₂S, 405.1631; found405.1637.

Example 105

This example illustrates a synthesis of2-(Trifluoromethoxy)-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB09-052, NCGC00244470-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.983 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.97 (s, 1H), 10.74 (s, 1H), 8.09-8.26 (m,2H), 7.91-8.03 (m, 1H), 7.83 (dd, J=7.8, 1.6 Hz, 1H), 7.77 (dd, J=7.6,2.0 Hz, 1H), 7.39-7.70 (m, 6H), 7.33 (td, J=7.6, 1.3 Hz, 1H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ ppm −56.63 (s, 3 F), −61.33 (s, 3 F); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₂H₁₅F₆N₂O₃, 468.0981; found 468.0982.

Example 106

This example illustrates a synthesis of2-Ethoxy-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB09-053, NCGC00244467-01, compound 99). The title compound wasprepared according to general protocol C. LC-MS Retention Time: t₁(Method 1)=6.998 min; ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 10.82(s, 1H), 8.51 (dd, J=8.4, 1.2 Hz, 1H), 8.28 (t, J=2.1 Hz, 1H), 7.89-8.07(m, 2H), 7.80 (dd, J=7.8, 1.6 Hz, 1H), 7.55-7.65 (m, 2H), 7.38-7.55 (m,2H), 7.27 (td, J=7.6, 1.3 Hz, 1H), 7.19 (dd, J=8.4, 1.0 Hz, 1H),7.01-7.12 (m, 1H), 4.30 (q, J=6.9 Hz, 2H), 1.30 (t, J=6.9 Hz, 3H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ ppm −61.40 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₃H₂₀F₃N₂O₃, 429.1421; found 429.1425.

Example 107

This example illustrates a synthesis of2-Nitro-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB09-055, NCGC00244468-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.695 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₅F₃N₃O₄, 430.1009; found 430.1009.

Example 108

This example illustrates a synthesis of2,6-Dimethoxy-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB09-056, NCGC00244474-01, CID-56593296). The title compound wasprepared according to general protocol C. LC-MS Retention Time: t₁(Method 1)=6.400 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.68 (s, 1H),10.62 (s, 1H), 8.43 (d, J=8.2 Hz, 1H), 8.08 (s, 1H), 7.93 (d, J=8.4 Hz,1H), 7.85 (dd, J=7.7, 1.1 Hz, 1H), 7.52-7.64 (m, 2H), 7.45 (d, J=7.6 Hz,1H), 7.34 (t, J=8.4 Hz, 1H), 7.27 (td, J=7.6, 1.1 Hz, 1H), 6.71 (d,J=8.4 Hz, 2H), 3.69 (s, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.29 (s,3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₄, 445.1370; found445.1380.

Example 109

This example illustrates a synthesis of Methyl2-(2-methoxybenzamido)benzoate (XJB09-051). A solution of2-aminobenzoate (2.57 mL, 19.9 mmol) in dichloromethane (50.0 mL) andTEA (8.30 mL, 59.5 mmol) was treated at 0° C. with 2-methoxybenzoylchloride (2.67 mL, 19.9 mmol). The reaction mixture was stirred at 0° C.for 2 h and at room temperature for 2 h. The reaction mixture wasconcentrated and purified via silica gel chromatography using a gradientof 0-50% of EtOAc in hexanes to give 5.50 g (97%) of the title productas a white solid. LC-MS Retention Time: t2 (Method 2)=3.761 min; m/z(M+H)⁺ 286.0.

Example 110

This example illustrates a synthesis of2-Methoxy-N-(2-((3-((trifluoromethyl)thio)phenyl)carbamoyl)phenyl)benzamide(XJB09-058, NCGC00244475-01, compound 158). The title compound wasprepared according to general protocol A. LC-MS Retention Time: t₁(Method 1)=7.128 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.53 (s, 1H),10.79 (s, 1H), 8.56 (dd, J=8.4, 1.2 Hz, 1H), 8.22-8.39 (m, 1H), 8.02(dd, J=7.8, 1.8 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.2 Hz, 1H), 7.78 (dd,J=7.8, 1.6 Hz, 1H), 7.50-7.64 (m, 3H), 7.43-7.49 (m, 1H), 7.26 (td,J=7.5, 1.2 Hz, 1H), 7.20 (dd, J=8.5, 1.1 Hz, 1H), 7.09 (ddd, J=7.9, 7.2,1.2 Hz, 1H), 3.97 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −41.91 (s, 3F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₈F₃N₂O₃S, 447.0985; found447.0984.

Example 111

This example illustrates a synthesis of2-Methoxy-N-(2-((3-(methylthio)phenyl)carbamoyl)phenyl)benzamide(XJB09-059, NCGC00244476-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.575 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.55 (s, 1H), 10.54 (s, 1H), 8.56 (dd,J=8.4, 1.2 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H), 7.67-7.86 (m, 2H),7.46-7.65 (m, 3H), 7.30 (t, J=7.9 Hz, 1H), 7.24 (td, J=7.6, 1.3 Hz, 1H),7.19 (dd, J=8.5, 1.1 Hz, 1H), 7.05-7.12 (m, 1H), 7.01 (ddd, J=7.8, 2.0,1.0 Hz, 1H), 3.98 (s, 3H), 2.46 (s, 3H); HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₂H₂₁N₂O₃S, 393.1267; found 393.1268.

Example 112

This example illustrates a synthesis of2-Methoxy-N-(2-((3-(piperidin-1-yl)phenyl)carbamoyl)phenyl)benzamide(XJB09-061, NCGC00244492-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=4.511 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.56 (br. s., 1H), 10.43 (br. s., 1H),8.56 (dd, J=8.4, 1.2 Hz, 1H), 8.01 (dd, J=7.8, 1.8 Hz, 1H), 7.62-7.80(m, 1H), 7.50-7.61 (m, 4H), 7.15-7.31 (m, 4H), 7.09 (ddd, J=7.9, 7.2,1.2 Hz, 1H), 3.98 (s, 3H), 3.10-3.33 (m, 4H), 1.60-1.78 (m, 4H),1.50-1.61 (m, 2H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₆H₂₈N₃O₃,430.2125; found 430.2135.

Example 113

This example illustrates a synthesis of2-(2-Methoxybenzamido)-N-methyl-N-(3-(trifluoromethyl)phenyl)benzamide(XJB09-062, NCGC00244493-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.442 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.65 (d, J=0.8 Hz, 1H), 8.21 (dt, J=8.4,0.6 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz, 1H), 7.54-7.66 (m, 2H), 7.37-7.54(m, 3H), 7.20-7.33 (m, 2H), 7.13 (ddd, J=7.9, 7.2, 1.0 Hz, 1H),7.04-7.11 (m, 1H), 6.86-6.96 (m, 1H), 4.02 (s, 3H), 3.44 (s, 3H); HRMS(ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₃, 429.1241; found 429.1418.

Example 114

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide(XJB09-067, NCGC00244477-01). The title compound was prepared accordingto general protocol G. LC-MS Retention Time: t₁ (Method 1)=6.964 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.83 (s, 1H), 10.16 (s, 1H), 8.57 (t,J=1.6 Hz, 1H), 8.26 (ddd, J=5.7, 3.7, 2.2 Hz, 1H), 7.93 (dd, J=8.3, 1.3Hz, 1H), 7.76-7.86 (m, 2H), 7.72 (dd, J=7.8, 1.6 Hz, 1H), 7.52 (ddd,J=8.5, 7.2, 1.6 Hz, 1H), 7.23 (td, J=7.6, 1.2 Hz, 1H), 2.16-2.36 (m,1H), 1.73-1.87 (m, 2H), 1.62-1.73 (m, 2H), 1.50-1.62 (m, 1H), 0.82-1.46(m, 5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −78.42 (s, 3 F); HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₁H₂₂F₃N₂O₄S, 455.1247; found 455.1253.

Example 115

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(3-(methylsulfonyl)phenyl)benzamide(XJB09-068, NCGC00244478-01). The title compound was prepared accordingto general protocol G. LC-MS Retention Time: t₁ (Method 1)=5.745 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.69 (s, 1H), 10.34 (s, 1H), 8.30-8.40 (m,1H), 8.11 (dd, J=8.3, 1.3 Hz, 1H), 8.00 (dt, J=7.2, 2.1 Hz, 1H), 7.76(dd, J=7.8, 1.6 Hz, 1H), 7.59-7.71 (m, 2H), 7.52 (ddd, J=8.5, 7.1, 1.6Hz, 1H), 7.22 (td, J=7.6, 1.3 Hz, 1H), 3.20 (s, 3H), 2.20-2.37 (m, 1H),1.75-1.91 (m, 2H), 1.65-1.75 (m, 2H), 1.52-1.64 (m, 1H), 0.95-1.45 (m,5H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₅N₂O₄S, 401.1530; found401.1524.

Example 116

This example illustrates a synthesis of2-Methoxy-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide(XJB09-069, NCGC00244479-01, compound 159). The title compound wasprepared according to general protocol G. LC-MS Retention Time: t₁(Method 1)=6.810 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58 (s, 1H),11.09 (s, 1H), 8.82 (t, J=2.1 Hz, 1H), 8.58 (dd, J=8.5, 1.3 Hz, 1H),8.23 (dt, J=7.0, 2.2 Hz, 1H), 8.02 (dd, J=7.7, 1.9 Hz, 1H), 7.76-7.99(m, 3H), 7.51-7.63 (m, 2H), 7.27 (td, J=7.5, 1.2 Hz, 1H), 7.22 (dd,J=8.4, 1.2 Hz, 1H), 7.09 (ddd, J=7.9, 7.2, 1.2 Hz, 1H), 3.99 (s, 3H);¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −78.39 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₂H₁₈F₃N₂O₅S, 479.0883; found 479.0886.

Example 117

This example illustrates a synthesis of2-Methoxy-N-(2-((3-(methylsulfonyl)phenyl)carbamoyl)phenyl)benzamide(XJB09-070, NCGC00244501-01). The title compound was prepared accordingto general protocol G. LC-MS Retention Time: t₁ (Method 1)=5.590 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.60 (s, 1H), 10.90 (s, 1H), 8.47-8.71 (m,2H), 7.93-8.16 (m, 2H), 7.81 (dd, J=7.8, 1.6 Hz, 1H), 7.62-7.72 (m, 2H),7.47-7.62 (m, 2H), 7.26 (td, J=7.6, 1.3 Hz, 1H), 7.21 (dd, J=8.5, 1.1Hz, 1H), 7.09 (ddd, J=7.9, 7.2, 1.0 Hz, 1H), 4.00 (s, 3H), 3.20 (s, 3H);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₁N₂O₅S, 425.1166; found 425.1169.

Example 118

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)benzamide(XJB09-073, NCGC00244494-01). The title compound was prepared accordingto general protocol E. LC-MS Retention Time: t₁ (Method 1)=7.588 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.51 (d, J=0.4 Hz, 1H), 10.48 (d, J=0.4Hz, 1H), 8.20 (dd, J=8.4, 1.2 Hz, 1H), 7.99-8.09 (m, 1H), 7.85 (s, 4H),7.75-7.82 (m, 2H), 7.46-7.59 (m, 3H), 7.22 (td, J=7.6, 1.3 Hz, 1H),2.18-2.35 (m, 1H), 1.77-1.89 (m, 2H), 1.64-1.75 (m, 2H), 1.51-1.64 (m,1H), 1.08-1.45 (m, 5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −60.89 (s, 3F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₆F₃N₂O₂, 467.1941; found467.1942.

Example 119

This example illustrates a synthesis of Methyl3-(cyclohexanecarboxamido)benzoate (XJB09-080). A solution of methyl3-aminobenzoate (0.903 mL, 6.62 mmol) in dichloromethane (10.0 mL) andtriethylamine (2.77 mL, 19.9 mmol) was treated at 0° C. withcyclohexanecarbonyl chloride (0.970 g, 6.62 mmol). The reaction mixturewas stirred at 0° C. for 2 h and at room temperature for 2 h. Thereaction mixture was concentrated and purified via silica gelchromatography using a gradient of 0-50% of EtOAc in hexanes to give1.61 g (94%) of the title product as a white solid which was useddirectly in the next reaction without further purification. LC-MSRetention Time: t₂ (Method 2)=3.676 min; m/z (M+H)⁺ 276.1.

Example 120

This example illustrates a synthesis of3-(Cyclohexanecarboxamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB09-097, NCGC00244495-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.516 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.53 (s, 1H), 10.00 (s, 1H), 8.21 (t,J=2.1 Hz, 1H), 8.14 (t, J=2.0 Hz, 1H), 8.03 (ddd, J=8.2, 1.2, 1.0 Hz,1H), 7.81 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.55-7.64 (m, 2H), 7.37-7.49(m, 2H), 2.24-2.41 (m, 1H), 1.69-1.92 (m, 4H), 1.57-1.69 (m, 1H),1.08-1.50 (m, 5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.29 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₂F₃N₂O₂, 391.1628; found 391.1637.

Example 121

This example illustrates a synthesis of Ethyl3-(cyclohexanecarboxamido)benzoate (XJB09-079). A solution of ethyl3-aminobenzoate (1.00 g, 6.05 mmol) in dichloromethane (10.0 mL) andtriethylamine (2.53 mL, 18.2 mmol) was treated at 0° C. with2-methoxybenzoyl chloride (0.814 mL, 6.05 mmol). The reaction mixturewas stirred at 0° C. for 2 h and at room temperature for 2 h. Thereaction mixture was concentrated and purified via silica gelchromatography using a gradient of 0-50% of EtOAc in hexanes to give1.11 g (61%) of the title product as a white solid which was useddirectly in the next reaction without further purification. LC-MSRetention Time: t₂ (Method 2)=3.664 min; m/z (M+H)⁺ 300.1.

Example 122

2-Methoxy-N-(3-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB09-098, NCGC00244496-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.471 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.58 (s, 1H), 10.30 (s, 1H), 8.27-8.35 (m,1H), 8.23 (t, J=2.1 Hz, 1H), 8.04 (dt, J=8.2, 1.1 Hz, 1H), 7.88-7.99 (m,1H), 7.67 (ddd, J=8.0, 1.4, 1.2 Hz, 1H), 7.63 (dd, J=7.6, 1.8 Hz, 1H),7.56-7.62 (m, 1H), 7.47-7.56 (m, 2H), 7.41-7.47 (m, 1H), 7.14-7.23 (m,1H), 7.06 (td, J=7.4, 1.0 Hz, 1H), 3.90 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₂H₁₈F₃N₂O₃, 415.1264; found 415.1275.

Example 123

This example illustrates a synthesis of Ethyl4-(2-methoxybenzamido)benzoate (XJB09-077). A solution of ethyl3-aminobenzoate (1.00 g, 6.05 mmol) in dichloromethane (10.0 mL) andtriethylamine (2.53 mL, 18.2 mmol) was treated at 0° C. with2-methoxybenzoyl chloride (0.814 mL, 6.05 mmol). The reaction mixturewas stirred at 0° C. for 2 h and at room temperature for 2 h. Thereaction mixture was concentrated and purified via silica gelchromatography using a gradient of 0-50% of EtOAc in hexanes to give1.77 g (98%) of the title product as a white solid which was useddirectly in the next reaction without further purification. LC-MSRetention Time: t₂ (Method 2)=3.683 min; m/z (M+H)⁺ 300.1.

Example 124

This example illustrates a synthesis of2-Methoxy-N-(4-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-001, NCGC00244497-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.452 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.43 (s, 1H), 10.39 (s, 1H), 8.24 (t,J=2.2 Hz, 1H), 8.02-8.10 (m, 1H), 7.95-8.02 (m, 2H), 7.80-7.94 (m, 2H),7.63 (dd, J=7.6, 1.8 Hz, 1H), 7.55-7.62 (m, 1H), 7.47-7.55 (m, 1H), 7.43(ddd, J=7.8, 1.9, 0.9 Hz, 1H), 7.19 (dd, J=8.5, 1.1 Hz, 1H), 7.07 (td,J=7.5, 1.1 Hz, 1H), 3.90 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−61.27 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₈F₃N₂O₃,415.1264; found 415.1269.

Example 125

This example illustrates a synthesis of Ethyl4-(cyclohexanecarboxamido)benzoate (XJB09-078). A solution of ethyl4-aminobenzoate (1.00 g, 6.05 mmol) in dichloromethane (10.0 mL) andtriethylamine (2.53 mL, 18.2 mmol) was treated at 0° C. withcyclohexanecarbonyl chloride (0.888 g, 6.05 mmol). The reaction mixturewas stirred at 0° C. for 2 h and at room temperature for 2 h. Thereaction mixture was concentrated and purified via silica gelchromatography using a gradient of 0-50% of EtOAc in hexanes to give1.58 g (95%) of the title product as a white solid which was useddirectly in the next reaction without further purification. LC-MSRetention Time: t₂ (Method 2)=3.687 min; m/z (M+H)⁺ 276.1.

Example 126

This example illustrates a synthesis of4-(Cyclohexanecarboxamido)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB10-015, NCGC00244480-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.473 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.37 (s, 1H), 10.09 (s, 1H), 8.23 (t,J=2.1 Hz, 1H), 8.03 (dd, J=8.4, 1.0 Hz, 1H), 7.85-7.97 (m, 2H),7.68-7.79 (m, 2H), 7.52-7.64 (m, 1H), 7.36-7.47 (m, 1H), 2.27-2.43 (m,1H), 1.69-1.94 (m, 4H), 1.58-1.69 (m, 1H), 1.10-1.51 (m, 5H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ ppm −61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₁H₂₂F₃N₂O₂, 391.1628; found 391.1631.

Example 127

This example illustrates a synthesis of2-(2-(Dimethylamino)ethoxy)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB10-024, NCGC00244498-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.204 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.49 (s, 1H), 8.11-8.39 (m, 1H), 7.76-7.99(m, 1H), 7.48-7.68 (m, 3H), 7.39-7.47 (m, 1H), 7.23 (dd, J=8.4, 0.8 Hz,1H), 7.13 (td, J=7.5, 1.0 Hz, 1H), 4.41 (dd, J=5.5, 4.5 Hz, 2H),3.41-3.57 (m, 2H), 2.80 (s, 6H); HRMS (ESI) m/z (M+H)⁺ calcd. forC₁₈H₂₀F₃N₂O₂, 353.1471; found 353.1474.

Example 128

This example illustrates a synthesis of Methyl2-(2-methoxy-N-methylbenzamido)benzoate (XJB10-022). A solution ofmethyl 2-(2-methoxybenzamido)benzoate (1.16 g, 4.07 mmol) in DMF (10.0mL) and was treated at 0° C. with NaH (0.813 g, 60%, 20.3 mmol). Thereaction mixture was warmed to room temperature and stirred at roomtemperature for 1 h. Then a solution of MeI (1.27 mL, 20.3 mmol) in DMF(4.00 mL) was added drop wise. The reaction mixture was stirred at roomtemperature for 1.5 h. The mixture was carefully quenched with water andextracted with EtOAc. The organic layer was separated, dried,concentrated to give the final product which was used directly in thenext reaction. LC-MS Retention Time: t₂ (Method 2)=3.293 min; m/z (M+H)⁺300.1.

Example 129

This example illustrates a synthesis of2-Methoxy-N-methyl-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-025, NCGC00244499-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.046 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₃, 429.1421; found 429.1438.

Example 130

This example illustrates a synthesis of2-Methoxy-N-methyl-N-(2-(methyl(3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-026, NCGC00244500-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=5.994 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₄H₂₂F₃N₂O₃, 443.1577; found 443.1579.

Example 131

This example illustrates a synthesis of2-Iodo-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-027, NCGC00244482-01). The title compound was prepared accordingto general protocol C. LC-MS Retention Time: t₁ (Method 1)=6.879 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₅F₃IN₂O₂, 511.0125; found511.0122.

Example 132

This example illustrates a synthesis of2-(2-(Dimethylamino)ethoxy)-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-028, NCGC00244483-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.705 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.11 (s, 1H), 10.84 (s, 1H), 8.41 (dd,J=8.5, 1.3 Hz, 1H), 8.07-8.20 (m, 1H), 7.96 (dd, J=8.0, 1.2 Hz, 1H),7.87 (dd, J=7.7, 1.9 Hz, 1H), 7.84 (dd, J=7.8, 1.8 Hz, 1H), 7.57-7.65(m, 2H), 7.52-7.57 (m, 1H), 7.45-7.52 (m, 1H), 7.24-7.33 (m, 2H), 7.13(td, J=7.5, 1.0 Hz, 1H), 4.55 (t, J=5.1 Hz, 2H), 3.49-3.74 (m, 2H), 2.78(s, 6H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₅F₃N₃O₃, 472.1843; found472.1851.

Example 133

This example illustrates a synthesis of2-(2-Methoxyethoxy)-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-029, NCGC00244484-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=6.625 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.22 (s,1H), 10.80 (s, 1H), 8.44 (dd, J=8.3, 1.3 Hz, 1H), 8.21 (t, J=2.2 Hz,1H), 7.93-7.99 (m, 1H), 7.91 (dd, J=7.8, 1.8 Hz, 1H), 7.80 (dd, J=7.7,1.7 Hz, 1H), 7.55-7.64 (m, 2H), 7.48-7.55 (m, 1H), 7.42-7.48 (m, 1H),7.27 (td, J=7.6, 1.3 Hz, 1H), 7.23 (dd, J=8.5, 1.1 Hz, 1H), 7.03-7.13(m, 1H), 4.26-4.37 (m, 2H), 3.61-3.72 (m, 2H), 3.11 (s, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ ppm −61.36 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₄H₂₂F₃N₂O₄, 459.1526; found 459.1527.

Example 134

This example illustrates a synthesis of2-(2-Methoxyethoxy)-N-(3-(trifluoromethyl)phenyl)benzamide (XJB10-030,NCGC00244485-01). The title compound was prepared according to generalprotocol H. LC-MS Retention Time: t₁ (Method 1)=6.644 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.45 (s, 1H), 8.08-8.29 (m, 1H), 7.93 (d, J=8.2 Hz,1H), 7.83 (dt, J=7.7, 1.8 Hz, 1H), 7.57-7.66 (m, 1H), 7.49-7.57 (m, 1H),7.40-7.49 (m, 1H), 7.20-7.28 (m, 1H), 7.05-7.18 (m, 1H), 4.31 (td,J=4.5, 1.9 Hz, 2H), 3.70-3.83 (m, 2H), 3.29 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −61.26 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₁₇H₁₇F₃NO₃, 340.1155; found 340.1162.

Example 135

This example illustrates a synthesis of tert-Butyl4-(2-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenoxy)ethyl)piperazine-1-carboxylate(XJB10-031, NCGC00244486-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.945 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₃₁F₃N₃O₄, 494.2261; found 494.2270.

Example 136

This example illustrates a synthesis of2-Isopropoxy-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-036, NCGC00244516-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=7.126 min;HRMS (ESI) m/z (M+H)⁺ calcd. For C₂₄H₂₂F₃N₂O₃, 443.1577; found 443.1599.

Example 137

This example illustrates a synthesis of2-Phenoxy-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-037, NCGC00244517-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=7.314 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.45 (s, 1H), 10.73 (s, 1H), 8.41-8.58 (m,1H), 8.11 (t, J=2.1 Hz, 1H), 7.97 (dd, J=7.8, 2.0 Hz, 1H), 7.85 (ddd,J=8.3, 2.2, 1.3 Hz, 1H), 7.80 (dd, J=7.8, 1.6 Hz, 1H), 7.42-7.65 (m,4H), 7.21-7.37 (m, 4H), 7.15 (tt, J=7.4, 1.2 Hz, 1H), 7.01-7.12 (m, 2H),6.84 (dd, J=8.2, 1.2 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.27(s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₀F₃N₂O₃, 477.1421; found477.1425.

Example 138

This example illustrates a synthesis of2-(2-(Piperidin-1-yl)ethoxy)-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-038, NCGC00244518-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.945 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₈H₂₉F₃N₃O₃, 512.2156; found 512.2172.

Example 139

This example illustrates a synthesis of2-(2-Morpholinoethoxy)-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-039, NCGC00244519-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.752 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₇F₃N₃O₄, 514.1948; found 514.1972.

Example 140

This example illustrates a synthesis of2-(2-(Piperidin-1-yl)ethoxy)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB10-040, NCGC00244519-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.527 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.57 (s, 1H), 8.23 (br. s., 1H), 7.89 (d,J=8.8 Hz, 1H), 7.49-7.66 (m, 3H), 7.45 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.4Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 4.24-4.54 (m, 2H), 3.40-3.61 (m, 4H),2.84-3.05 (m, 2H), 1.44-1.80 (m, 5H), 1.21-1.35 (m, 1H); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₇H₂₇F₃N₃O₄, 514.1948; found 514.1972.

Example 141

This example illustrates a synthesis of2-(2-Morpholinoethoxy)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB10-041, NCGC00244502-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.280 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂F₃N₂O₃, 395.1577; found 395.1585.

Example 142

This example illustrates a synthesis of2-(Cyclohexanecarboxamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)benzamide(XJB10-042, NCGC00244503-01). The title compound was prepared accordingto general protocol E. LC-MS Retention Time: t₁ (Method 1)=7.417 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.46 (s, 1H), 10.40 (s, 1H), 8.15 (dd,J=8.3, 1.3 Hz, 1H), 7.83 (dt, J=7.7, 0.8 Hz, 1H), 7.66-7.79 (m, 4H),7.57-7.65 (m, 1H), 7.45-7.57 (m, 1H), 7.33-7.45 (m, 2H), 7.20 (td,J=7.6, 1.3 Hz, 1H), 7.05 (dd, J=7.6, 1.0 Hz, 1H), 2.18-2.36 (m, 1H),1.73-1.88 (m, 2H), 1.63-1.74 (m, 2H), 1.50-1.63 (m, 1H), 0.99-1.42 (m,5H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −55.34 (s, 3 F); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₇H₂₆F₃N₂O₂, 467.1941; found 467.1931.

Example 143

This example illustrates a synthesis of2-(2-(Piperazin-1-yl)ethoxy)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB10-043, NCGC00244504-01). A solution of tert-butyl4-(2-(2-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)ethyl)piperazine-1-carboxylate(0.099 g, 0.200 mmol) in dichloromethane (2.00 mL) was treated at 0° C.with TFA (1.00 mL). The reaction mixture was stirred at 0° C. for 1 h.The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filteredand purified via C₁₈ reverse phase HPLC to give the final product. LC-MSRetention Time: t₁ (Method 1)=3.872 min; HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₀H₂₃F₃N₃O₂, 394.1737; found 394.1745.

Example 144

This example illustrates a synthesis of2-Methoxy-N-(2-((3-(thiophen-2-yl)phenyl)carbamoyl)phenyl)benzamide(XJB10-044, NCGC00244505-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.455 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₁N₂O₃S, 429.1267; found 429.1285.

Example 145

This example illustrates a synthesis of2-(3-(Dimethylamino)propoxy)-N-(3-(trifluoromethyl)phenyl)benzamide(XJB10-045, NCGC00244506-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.371 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.27-10.74 (m, 1H), 8.25 (s, 1H), 7.92 (d,J=7.4 Hz, 1H), 7.55-7.65 (m, 2H), 7.48-7.54 (m, 1H), 7.44 (d, J=7.8 Hz,1H), 7.17 (d, J=8.4 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 4.16 (t, J=5.5 Hz,2H), 3.04-3.21 (m, 2H), 2.68 (s, 6H), 1.97-2.18 (m, 2H); HRMS (ESI) m/z(M+H)⁺ calcd. for C₁₉H₂₂F₃N₂O₂, 367.1628; found 367.1628.

Example 146

This example illustrates a synthesis of2-(3-(Dimethylamino)propoxy)-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-046, NCGC00244507-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.868 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₆H₂₇F₃N₃O₃, 486.1999; found 486.2002.

Example 147

This example illustrates a synthesis of tert-Butyl4-(2-(2-((2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)carbamoyl)phenoxy)ethyl)piperazine-1-carboxylate(XJB10-047, NCGC00244481-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=5.211 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₃₂H₃₆F₃N₄O₅, 613.2632; found 613.2642.

Example 148

This example illustrates a synthesis ofN-(2-((3-(Trifluoromethyl)phenyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-7-carboxamide(XJB10-049, NCGC00244508-01). The title compound was prepared accordingto general protocol H. LC-MS Retention Time: t₁ (Method 1)=4.777 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₆F₃N₄O₂, 425.1220; found 425.1227.

Example 149

This example illustrates a synthesis of2-(2-(Piperazin-1-yl)ethoxy)-N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide(XJB10-050, NCGC00244509-01). A solution of tert-butyl4-(2-(2-(2-(3-(trifluoromethyl)phenylcarbamoyl)phenylcarbamoyl)phenoxy)ethyl)piperazine-1-carboxylate(50.0 mg, 0.082 mmol) in dichloromethane (2.00 mL) was treated at 0° C.with TFA (1.00 mL). The reaction mixture was stirred at 0° C. for 1 h.The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filteredand purified via C₁₈ reverse phase HPLC to give the final product. LC-MSRetention Time: t₁ (Method 1)=4.303 min; HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₇H₂₈F₃N₄O₃, 513.2108; found 513.2128.

Example 150

This example illustrates a synthesis of Methyl2-(2-ethoxybenzamido)benzoate (XJB11-036). A solution of ethyl methyl2-aminobenzoate (1.29 mL, 9.92 mmol) in dichloromethane (25.0 mL) andtriethylamine (4.15 mL, 29.8 mmol) was treated at 0° C. with2-ethoxybenzoyl chloride (1.83 g, 9.92 mmol). The reaction mixture wasstirred at 0° C. for 2 h and at room temperature for 2 h. The reactionmixture was concentrated and purified via silica gel chromatographyusing a gradient of 0-50% of EtOAc in hexanes to give 2.70 g (91%) ofthe title product as a white solid which was used directly in the nextreaction without further purification. LC-MS Retention Time: t₂ (Method2)=3.908 min; m/z (M+H)⁺ 300.1.

Example 151

This example illustrates a synthesis of2-Ethoxy-N-(2-(pyridin-2-ylcarbamoyl)phenyl)benzamide (XJB11-037,NCGC00250128-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=5.072 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.30 (s, 1H), 11.01 (s, 1H), 8.46 (d, J=8.2 Hz,1H), 8.37 (dd, J=5.1, 2.3 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.92 (dd,J=7.6, 2.2 Hz, 1H), 7.82-7.89 (m, 1H), 7.79 (dd, J=7.8, 2.0 Hz, 1H),7.44-7.61 (m, 2H), 7.13-7.25 (m, 3H), 7.02-7.10 (m, 1H), 4.28 (q, J=6.9Hz, 2H), 1.29 (t, J=7.0 Hz, 3H); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₁H₂₀N₃O₃, 362.1499; found 362.1505.

Example 152

This example illustrates a synthesis of2-Ethoxy-N-(2-(pyridin-4-ylcarbamoyl)phenyl)benzamide (XJB11-039,NCGC00250119-02). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=4.341 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.01 (s, 1H), 10.65 (s, 1H), 8.17-8.36 (m, 3H),7.72 (dd, J=7.8, 2.0 Hz, 1H), 7.57 (dd, J=7.6, 1.8 Hz, 1H), 7.51 (dd,J=4.9, 1.8 Hz, 2H), 7.38 (td, J=7.9, 1.8 Hz, 1H), 7.31 (ddd, J=8.5, 7.1,2.0 Hz, 1H), 7.03-7.10 (m, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.68-6.91 (m,1H), 4.09 (q, J=6.8 Hz, 2H), 1.11 (t, J=6.8 Hz, 3H); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₁H₂₀N₃O₃, 362.1499; found 362.1499.

Example 153

This example illustrates a synthesis ofN-(3-(tert-Butyl)phenyl)-2-(2-ethoxybenzamido)benzamide (XJB11-040,NCGC00250129-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=7.379 min; HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₆H₂₉N₂O₃, 417.2173; found 417.2175.

Example 154

This example illustrates a synthesis of2-Ethoxy-N-(2-(pyridin-4-ylcarbamoyl)phenyl)benzamide (XJB11-041,NCGC00250107-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=7.305 min; HRMS (ESI)m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₃S, 461.1141; found 461.1146.

Example 155

This example illustrates a synthesis of2-Ethoxy-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide(XJB11-043, NCGC00250130-01, compound 174). The title compound wasprepared according to general protocol A. LC-MS Retention Time: t₁(Method 1)=6.963 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₅S,493.1040; found 493.1044.

Example 156

This example illustrates a synthesis of2-Ethoxy-N-(2-(pyridin-3-ylcarbamoyl)phenyl)benzamide (XJB11-047,NCGC00250104-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=4.330 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.32 (s, 1H), 10.71 (s, 1H), 8.89 (d, J=2.3 Hz,1H), 8.51 (d, J=8.2 Hz, 1H), 8.31 (dd, J=4.7, 1.6 Hz, 1H), 8.13 (ddd,J=8.7, 2.4, 1.4 Hz, 1H), 7.92 (dd, J=7.8, 2.0 Hz, 1H), 7.80 (dd, J=7.8,2.0 Hz, 1H), 7.54-7.63 (m, 1H), 7.51 (td, J=7.8, 2.0 Hz, 1H), 7.39 (dd,J=8.2, 4.7 Hz, 1H), 7.22-7.32 (m, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.06 (t,J=7.4 Hz, 1H), 4.27 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H); HRMS(ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₀N₃O₃, 362.1499; found 362.1507.

Example 157

This example illustrates a synthesis of2-Ethoxy-N-(2-((5-iodopyridin-3-yl)carbamoyl)phenyl)benzamide(XJB11-048, NCGC00250103-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.305 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.31 (s, 1H), 10.78 (s, 1H), 8.85 (d,J=2.3 Hz, 1H), 8.63 (t, J=2.3 Hz, 1H), 8.54 (d, J=2.3 Hz, 1H), 8.49 (d,J=8.2 Hz, 1H), 7.93 (dd, J=7.8, 2.0 Hz, 1H), 7.80 (dd, J=7.8, 2.0 Hz,1H), 7.59 (td, J=7.9, 1.8 Hz, 1H), 7.52 (ddd, J=8.6, 7.0, 2.0 Hz, 1H),7.23-7.31 (m, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 4.31(q, J=6.8 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H); HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₁H₁₉IN₃O₃, 488.0466; found 488.0475.

Example 158

This example illustrates a synthesis of Methyl4-(2-ethoxybenzamido)nicotinate (XJB11-044). A solution of4-aminonicotinate (500 mg, 3.29 mmol) in dichloromethane (25.0 mL) andtriethylamine (1.37 mL, 9.86 mmol) was treated at 0° C. with2-ethoxybenzoyl chloride (607 mg, 3.29 mmol). The reaction mixture wasstirred at 0° C. for 2 h and at room temperature for 2 h. The reactionmixture was concentrated and purified via silica gel chromatographyusing a gradient of 0-100% of EtOAc in hexanes to give 924 mg (94%) ofthe title product as a white solid which was used directly in the nextreaction without further purification. LC-MS Retention Time: t₂ (Method2)=3.045 min; m/z (M+H)⁺ 301.1.

Example 159

This example illustrates a synthesis of4-(2-Ethoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)nicotinamide(XJB11-049, NCGC00250117-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=5.507 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.71 (s, 1H), 11.25 (s, 1H), 9.00 (s, 1H),8.77 (t, J=2.2 Hz, 1H), 8.65-8.71 (m, 1H), 8.54-8.64 (m, 1H), 8.15-8.26(m, 1H), 7.96 (dd, J=7.8, 2.3 Hz, 1H), 7.78-7.93 (m, 2H), 7.56 (ddd,J=8.6, 7.0, 2.0 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 7.09 (t, J=7.4 Hz, 1H),4.35 (q, J=6.9 Hz, 2H), 1.29 (t, J=6.8 Hz, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −78.37 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₂H₁₉F₃N₃O₅S, 494.0992; found 494.1004.

Example 160

This example illustrates a synthesis of Methyl2-(2-ethoxybenzamido)nicotinate (XJB11-045). A solution of4-aminonicotinate (500 mg, 3.29 mmol) in dichloromethane (25.0 mL) andtriethylamine (1.37 mL, 9.86 mmol) was treated at 0° C. with2-ethoxybenzoyl chloride (607 mg, 3.29 mmol). The reaction mixture wasstirred at 0° C. for 2 h and at room temperature for 2 h. The reactionmixture was concentrated and purified via silica gel chromatographyusing a gradient of 0-100% of EtOAc in hexanes to give 840 mg (85%) ofthe title product as a white solid which was used directly in the nextreaction without further purification. LC-MS Retention Time: t₂ (Method2)=2.975 min; m/z (M+H)⁺ 301.1.

Example 161

This example illustrates a synthesis of2-(2-Ethoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)nicotinamide(XJB11-050, NCGC00250118-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=5.472 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.98 (s, 1H), 10.81 (s, 1H), 8.47-8.66 (m,2H), 8.05-8.24 (m, 2H), 7.75-7.87 (m, 2H), 7.72 (dd, J=7.8, 2.0 Hz, 1H),7.51 (ddd, J=8.5, 7.1, 2.0 Hz, 1H), 7.39 (dd, J=7.6, 4.9 Hz, 1H), 7.20(d, J=8.2 Hz, 1H), 7.00 (t, J=7.4 Hz, 1H), 4.27 (q, J=7.0 Hz, 2H), 1.42(t, J=7.0 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −78.44 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₉F₃N₃O₅S, 494.0992; found494.1004.

Example 162

This example illustrates a synthesis of2-Ethoxy-N-(2-((3-iodophenyl)carbamoyl)phenyl)benzamide (XJB11-053,NCGC00250105-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=7.114 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.31 (s, 1H), 10.59 (s, 1H), 8.50 (d, J=8.2 Hz,1H), 8.27 (t, J=2.0 Hz, 1H), 7.94 (dd, J=7.8, 2.0 Hz, 1H), 7.75 (dd,J=7.6, 1.8 Hz, 1H), 7.69 (dd, J=8.2, 2.3 Hz, 1H), 7.41-7.60 (m, 3H),7.10-7.29 (m, 3H), 7.00-7.11 (m, 1H), 4.31 (q, J=7.0 Hz, 2H), 1.33 (t,J=7.0 Hz, 3H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₀IN₂O₃, 487.0513;found 487.0514.

Example 163

This example illustrates a synthesis of Methyl2-(2-iodobenzamido)benzoate (XJB11-035). A solution of methyl2-aminobenzoate (1.29 mL, 9.92 mmol) in dichloromethane (25.0 mL) andtriethylamine (4.15 mL, 29.8 mmol) was treated at 0° C. with2-iodobenzoyl chloride (2.64 g, 9.92 mmol).²² The reaction mixture wasstirred at 0° C. for 2 hours and at room temperature for another 2hours. The reaction mixture was concentrated in vacuo and the cruderesidue was purified via silica gel chromatography using a gradient of0-50% of EtOAc in hexanes to give 3.40 g (90%) of the title compound asa white solid. LC-MS Retention Time: t₁ (Method 1)=6.308 min; t₂ (Method2)=3.744 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.97 (s, 1H), 8.33 (d,J=8.2 Hz, 1H), 7.87-8.01 (m, 2H), 7.63-7.73 (m, 1H), 7.46-7.62 (m, 2H),7.13-7.33 (m, 2H), 3.82 (s, 3H); HRMS (ESI) m/z (M+H)⁺ calcd. forC₁₅H₁₃INO₃, 381.9935; found 381.9943.

Example 164

This example illustrates a synthesis of2-Iodo-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide(XJB11-054, NCGC00250120-01). A solution of methyl2-(2-iodobenzamido)benzoate (500 mg, 1.31 mmol) in toluene (15.0 mL) wastreated at room temperature with 3-(trifluoromethylsulfonyl)aniline (443mg, 1.97 mmol) followed by trimethylaluminum (1.31 mL, 2.0 M in toluene,2.62 mmol). The reaction mixture was stirred at 100° C. overnight. Aftercooling, the reaction mixture was concentrated in vacuo; and the cruderesidue was purified via silica gel chromatography using a gradient of0-50% of EtOAc in hexanes to give 677 mg (90%) of the title compound asa white solid. LC-MS Retention Time: t₁ (Method 1)=6.816 min; t₂ (Method2)=3.857 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.96 (s, 1H), 10.69 (s,1H), 8.57 (s, 1H), 8.17-8.36 (m, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.91 (d,J=7.8 Hz, 1H), 7.70-7.86 (m, 3H), 7.61 (t, J=7.4 Hz, 1H), 7.41-7.56 (m,2H), 7.34 (t, J=7.6 Hz, 1H), 7.11-7.27 (m, 1H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −78.38 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₁H₁₅F₃₁N₂O₄S, 574.9744; found 574.9752.

Example 165

This example illustrates a synthesis of Methyl3-(2-ethoxybenzamido)isonicotinate (XJB11-046). A solution of methyl3-aminoisonicotinate (200 mg, 1.31 mmol) in dichloromethane (25.0 mL)and triethylamine (0.550 mL, 3.94 mmol) was treated at 0° C. with2-ethoxybenzoyl chloride (243 mg, 1.31 mmol). The reaction mixture wasstirred at 0° C. for 2 h and at room temperature for 2 h. The reactionmixture was concentrated and purified via silica gel chromatographyusing a gradient of 0-100% of EtOAc in hexanes to give 45 mg (11%) ofthe title product as a white solid which was used directly in the nextreaction without further purification.

Example 166

This example illustrates a synthesis of3-(2-Ethoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)isonicotinamide(XJB11-055, NCGC00250121-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=5.766 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₁₉F₃N₃O₅S, 494.0992; found494.1000.

Example 167

This example illustrates a synthesis of Methyl3-(2-ethoxybenzamido)picolinate (XJB11-056). A solution of methyl3-aminopicolinate (500 mg, 3.29 mmol) in dichloromethane (25.0 mL) andtriethylamine (1.37 mL, 9.86 mmol) was treated at 0° C. with2-ethoxybenzoyl chloride (607 mg, 3.29 mmol). The reaction mixture wasstirred at 0° C. for 2 h and at room temperature for 2 h. The reactionmixture was concentrated and purified via silica gel chromatographyusing a gradient of 0-100% of EtOAc in hexanes to give 741 mg (75%) ofthe title product as a white solid which was used directly in the nextreaction without further purification. LC-MS Retention Time: t₂ (Method2)=3.519 min; m/z (M+H)⁺ 301.1.

Example 168

This example illustrates a synthesis of2-(2-Ethoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)nicotinamide(XJB11-058, NCGC00250122-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=7.402 min;HRMS (ESI) m/z (M+Na)⁺ calcd. for C₂₂H₁₈F₃N₃NaO₅S, 516.0811; found516.0837.

Example 169

This example illustrates a synthesis of Methyl2-(2-ethoxybenzamido)thiophene-3-carboxylate (XJB11-057). A solution of2-aminothiophene-3-carboxylate (500 mg, 3.18 mmol) in dichloromethane(25.0 mL) and triethylamine (1.33 mL, 9.54 mmol) was treated at 0° C.with 2-ethoxybenzoyl chloride (587 mg, 3.18 mmol). The reaction mixturewas stirred at 0° C. for 2 h and at room temperature for 2 h. Thereaction mixture was concentrated and purified via silica gelchromatography using a gradient of 0-100% of EtOAc in hexanes to give798 mg (82%) of the title product as a white solid which was useddirectly in the next reaction without further purification.

Example 170

This example illustrates a synthesis of2-(2-Ethoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)thiophene-3-carboxamide(XJB11-059, NCGC00250123-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=7.341 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₁₈F₃N₂O₅S₂, 499.0604; found499.0608.

Example 171

This example illustrates a synthesis of Methyl2-(2-ethoxyphenylsulfonamido)benzoate (XJB11-060). A solution of methyl2-aminobenzoate (206 mg, 1.359 mmol) in dichloromethane (5.00 mL) andtriethylamine (0.568 mL, 4.08 mmol) was treated at 0° C. with2-ethoxybenzene-1-sulfonyl chloride (300 mg, 1.359 mmol). The reactionmixture was stirred at 0° C. for 2 h and at room temperature for 2 h.The reaction mixture was concentrated and purified via silica gelchromatography using a gradient of 0-100% of EtOAc in hexanes to give274 mg (60%) of the title product as a white solid which was useddirectly in the next reaction without further purification. LC-MSRetention Time: t₂ (Method 2)=3.698 min; m/z (M+H)⁺ 336.1.

Example 172

This example illustrates a synthesis of2-(2-Ethoxyphenylsulfonamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide(XJB11-062, NCGC00250124-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.631 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₀F₃N₂O₆S₂, 529.0709; found529.0716.

Example 173

This example illustrates a synthesis ofN-(2-amino-5-(trifluoromethyl)phenyl)-2-(2-ethoxybenzamido)benzamide(XJB11-063, NCGC00250125-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.408 min; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.43 (s, 1H), 9.89 (s, 1H), 8.48 (d, J=7.8Hz, 1H), 7.88 (dd, J=7.8, 2.0 Hz, 2H), 7.53-7.61 (m, 1H), 7.49 (td,J=7.8, 2.0 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.14(d, J=8.2 Hz, 1H), 6.98-7.08 (m, 2H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 5.46(s, 2H), 4.20 (q, J=6.9 Hz, 2H), 1.26 (t, J=6.8 Hz, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −60.99 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₂₃H₂₁F₃N₃O₃, 444.1530; found 444.1536.

Example 174

This example illustrates a synthesis of Ethyl3-(2-ethoxybenzamido)propanoate (XJB11-061). A solution of ethyl3-aminopropanoate, HCl salt (300 mg, 1.95 mmol) in dichloromethane (25.0mL) and triethylamine (0.817 mL, 5.86 mmol) was treated at 0° C. with2-ethoxybenzoyl chloride (361 mg, 1.95 mmol). The reaction mixture wasstirred at 0° C. for 2 h and at room temperature for 2 h. The reactionmixture was concentrated and purified via silica gel chromatographyusing a gradient of 0-100% of EtOAc in hexanes to give 478 mg (92%) ofthe title product as a colorless oil which was used directly in the nextreaction without further purification. LC-MS Retention Time: t₂ (Method2)=3.346 min; m/z (M+H)⁺ 266.1.

Example 175

This example illustrates a synthesis of2-Ethoxy-N-(3-oxo-3-((3-((trifluoromethyl)sulfonyl)phenyl)amino)propyl)benzamide(XJB11-064, NCGC00250126-01, CID-56593338). The title compound wasprepared according to general protocol A. LC-MS Retention Time: t₁(Method 1)=5.985 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H),8.62 (s, 1H), 8.39 (t, J=5.9 Hz, 1H), 7.93-8.07 (m, 1H), 7.82 (dd,J=7.8, 2.0 Hz, 1H), 7.78 (d, J=5.5 Hz, 2H), 7.38-7.48 (m, 1H), 7.08 (d,J=8.6 Hz, 1H), 6.96-7.04 (m, 1H), 4.09 (q, J=6.8 Hz, 2H), 3.61 (q, J=6.0Hz, 2H), 2.68 (t, J=6.3 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −78.46 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. forC₁₉H₂₀F₃N₂O₅S, 445.1040; found 445.1042.

Example 176

This example illustrates a synthesis of Mixture of6-(2-ethoxyphenyl)-10-(trifluoromethyl)benzo[4,5]imidazo[1,2-c]quinazolineand6-(2-ethoxyphenyl)-9-(trifluoromethyl)benzo[4,5]imidazo[1,2-c]quinazoline(XJB11-067-2, NCGC00250127-01). A solution ofN-(2-amino-5-(trifluoromethyl)phenyl)-2-(2-ethoxybenzamido)benzamide(30.0 mg, 0.068 mmol) in glacial acetic acid (1.00 mL) was heated at 70°C. for 16 h. The mixture was concentrated, re-dissolved in 2.00 mL ofDMSO, filtered and purified via C₁₈ reverse phase HPLC to give the finalproducts as a mixture.

Example 177

This example illustrates a synthesis of2-Propoxy-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide(XJB11-068, NCGC00250109-01, compound 179). The title compound wasprepared according to general protocol H. LC-MS Retention Time: t₁(Method 1)=7.147 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₄H₂₂F₃N₂O₅S,507.1196; found 507.1219.

Example 178

This example illustrates a synthesis of2-Ethoxy-N-(2-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzamide(XJB11-069, NCGC00250108-01). A solution ofN-(2-amino-5-(trifluoromethyl)phenyl)-2-(2-ethoxybenzamido)benzamide(30.0 mg, 0.068 mmol) in glacial acetic acid (1.00 mL) was stirred atroom temperature for 24 h. The mixture was concentrated, re-dissolved in2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC togive the final products. LC-MS Retention Time: t₁ (Method 1)=6.588 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₁₉F₃N₃O₂, 426.1424; found 426.1437.

Example 179

This example illustrates a synthesis of2-Butoxy-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide(XJB11-070, NCGC00250110-01, compound 180). The title compound wasprepared according to general protocol H. LC-MS Retention Time: t₁(Method 1)=7.325 min; t₂ (Method 2)=3.971 min; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 11.25 (s, 1H), 11.09 (s, 1H), 8.69 (s, 1H), 8.53 (d, J=8.6 Hz,1H), 8.24 (ddd, J=7.2, 2.2, 2.0 Hz, 1H), 7.91 (dd, J=7.8, 2.0 Hz, 1H),7.77-7.89 (m, 3H), 7.60 (td, J=7.8, 1.6 Hz, 1H), 7.43-7.56 (m, 1H), 7.28(td, J=7.5, 1.0 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 7.00-7.11 (m, 1H), 4.18(t, J=6.8 Hz, 2H), 1.54-1.75 (m, 2H), 1.21 (sxt, J=7.4 Hz, 2H), 0.69 (t,J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −78.42 (s, 3 F); HRMS(ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₄F₃N₂O₅S, 521.1353; found 521.1359.

Example 180

This example illustrates a synthesis of2-(2,2,2-Trifluoroethoxy)-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide(XJB11-071, NCGC00250111-01, compound 177). The title compound wasprepared according to general protocol H. LC-MS Retention Time: t₁(Method 1)=6.804 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.07 (s, 1H),11.03 (s, 1H), 8.61 (t, J=2.2 Hz, 1H), 8.41 (d, J=8.2 Hz, 1H), 8.19-8.33(m, 1H), 7.70-7.94 (m, 4H), 7.58-7.67 (m, 1H), 7.47-7.58 (m, 1H), 7.35(d, J=8.6 Hz, 1H), 7.26-7.33 (m, 1H), 7.17 (t, J=7.4 Hz, 1H), 4.92 (q,J=9.0 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −72.45 (s, 3 F), −78.46(s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₁₇F₆N₂O₅S, 547.0757;found 547.0762.

Example 181

This example illustrates a synthesis of2-(Ethylthio)-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide(XJB11-072, NCGC00250106-01, CID-56593341). A tube was charged with CuI(3.3 mg, 0.017 mmol), 1,10-phenanthroline (6.3 mg, 0.035 mmol), (56.7mg, 0.174 mmol),2-iodo-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide(50.0 mg, 0.087 mmol) and ethanethiol (10.8 mg, 0.174 mmol) in toluene(1.50 mL) under N₂. The tube was sealed and the reaction mixture wasstirred at 110° C. for 24 h. The resulting mixture was cooled to roomtemperature and treated with a small portion of Si-THIOL to get rid ofcopper. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO,filtered and purified via C₁₈ reverse phase HPLC to give the finalproduct. LC-MS Retention Time: t₁ (Method 1)=6.910 min; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.95 (s, 1H), 10.73 (s, 1H), 8.55 (s, 1H), 8.28 (dt,J=6.7, 2.0 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.74-7.91 (m, 3H), 7.57-7.66(m, 1H), 7.51-7.57 (m, 1H), 7.39-7.48 (m, 2H), 7.31 (td, J=7.6, 1.2 Hz,1H), 7.24 (ddd, J=7.4, 4.9, 3.7 Hz, 1H), 2.90 (q, J=7.3 Hz, 2H), 1.13(t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −78.40 (s, 3 F);HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₄S₂, 509.0811; found509.0814.

Example 182

This example illustrates a synthesis of Methyl2-(2-isopropoxybenzamido)benzoate (XJB12-040). A solution of methyl2-aminobenzoate (0.245 mL, 1.89 mmol) in dichloromethane (8.00 mL) andtriethylamine (0.53 mL, 3.78 mmol) was treated at 0° C. with2-isopropoxybenzoyl chloride (250 mg, 1.26 mmol). The reaction mixturewas stirred at 0° C. for 2 hours and then at room temperature foranother 2 hours. The reaction mixture was concentrated in vacuo and thecrude residue was purified via silica gel chromatography using agradient of 0-50% of EtOAc in hexanes to give 320 mg (81%) of the titlecompound as a colorless oil. LC-MS Retention Time: t₁ (Method 1)=6.576min; t₂ (Method 2)=3.825 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.59 (s,1H), 8.63 (d, J=8.6 Hz, 1H), 7.98 (dd, J=7.8, 1.6 Hz, 1H), 7.83 (dd,J=7.8, 2.0 Hz, 1H), 7.64 (ddd, J=8.5, 7.1, 1.6 Hz, 1H), 7.45-7.56 (m,1H), 7.13-7.27 (m, 2H), 6.94-7.09 (m, 1H), 4.82 (dq, J=6.3, 6.0 Hz, 1H),3.85 (s, 3H), 1.35 (d, J=5.9 Hz, 6H); HRMS (ESI) m/z (M+H)⁺ calcd. forC₁₈H₂₀NO₄, 314.1387; found 314.1399.

Example 183

This example illustrates a synthesis of2-Isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide(XJB11-073, NCGC00250135-01, compound 178). A W tube was charged withcopper (I) iodide (3.3 mg, 0.017 mmol), 1,10-phenanthroline (6.3 mg,0.035 mmol), cesium carbonate (56.7 mg, 0.174 mmol),2-iodo-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide(50.0 mg, 0.087 mmol), propan-2-ol (10.5 mg, 0.174 mmol), and drytoluene (1.50 mL). The tube was sealed, and the reaction mixture wasstirred at 110° C. for overnight. The resulting suspension was cooled toroom temperature and treated with Si-Thio. The reaction mixture wasfiltered and concentrated in vacuo to give an orange oil that was takenup in 1.5 mL of DMSO and purified via C₁₈ reverse phase HPLC to give 1.7mg (4%) of the title compound as a white solid. LC-MS Retention Time: t₁(Method 1)=6.974 min; t₂ (Method 2)=3.881 min; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 11.08 (br. s., 1H), 11.07 (s, 1H), 8.73 (s, 1H), 8.46 (d, J=8.2Hz, 1H), 8.18 (dt, J=7.4, 2.0 Hz, 1H), 7.89 (dd, J=7.8, 1.6 Hz, 1H),7.77-7.87 (m, 3H), 7.57-7.63 (m, 1H), 7.49 (ddd, J=8.7, 7.1, 1.8 Hz,1H), 7.28 (td, J=7.5, 1.0 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.03 (t,J=7.6 Hz, 1H), 4.79 (m, 1H), 1.31 (d, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) dppm −78.36 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₄H₂₂F₃N₂O₅S,507.1196; found 507.1221.

Or a solution of methyl 2-(2-isopropoxybenzamido)benzoate (110 mg, 0.351mmol) in toluene (4.00 mL) was treated with3-(trifluoromethylsulfonyl)aniline (119 mg, 0.527 mmol) at roomtemperature, followed by trimethylaluminum (0.503 mL, 2.0 M in toluene,1.06 mmol). The reaction mixture was stirred at 100° C. for overnight.After cooling, the reaction mixture was concentrated in vacuo; and thecrude residue was purified via silica gel chromatography using agradient of 0-80% of EtOAc in hexanes to give 130 mg (73%) of the titlecompound as a white solid.

Example 184

This example illustrates a synthesis of(E)-2-Ethoxy-N-(2-((3-(prop-1-en-1-yl)phenyl)carbamoyl)phenyl)benzamide(XJB11-074, NCGC00250131-01). A mixture of2-ethoxy-N-(2-(3-iodophenylcarbamoyl)phenyl)benzamide (50.0 mg, 0.103mmol), (E)-prop-1-enylboronic acid (13.3 mg, 0.154 mmol) and Pd(PPh₃)₄(5.9 mg, 5.14 μmol) in DMF (1.50 mL) and 2.0 N Na₂CO₃ (0.500 mL) aqueoussolution was heated in μW at 100° C. for 30 min. The reaction was cooledto room temperature, added a small portion of Si-THIOL to get rid ofPalladium. The mixture was filtered and purified via C₁₈ reverse phaseHPLC to give the final product. LC-MS Retention Time: t₁ (Method1)=7.093 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.35 (s, 1H), 10.48 (s,1H), 8.51 (d, J=8.2 Hz, 1H), 7.93 (dd, J=7.8, 2.0 Hz, 1H), 7.70-7.82 (m,2H), 7.42-7.63 (m, 3H), 7.21-7.33 (m, 2H), 7.18 (d, J=8.6 Hz, 1H), 7.12(d, J=7.8 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 6.33-6.46 (m, 1H), 6.16-6.32(m, 1H), 4.28 (q, J=7.0 Hz, 2H), 1.84 (dd, J=6.7, 1.6 Hz, 3H), 1.30 (t,J=7.0 Hz, 3H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₅N₂O₃, 401.1860;found 401.1859.

Example 185

This example illustrates a synthesis of(Z)-2-Ethoxy-N-(2-((3-(prop-1-en-1-yl)phenyl)carbamoyl)phenyl)benzamide(XJB11-075, NCGC00250132-01). A mixture of2-ethoxy-N-(2-(3-iodophenylcarbamoyl)phenyl)benzamide (50.0 mg, 0.103mmol), (Z)-prop-1-enylboronic acid (13.3 mg, 0.154 mmol) and Pd(PPh₃)₄(5.9 mg, 5.14 μmol) in DMF (1.50 mL) and 2.0 N Na₂CO₃ (0.500 mL) aqueoussolution was heated in W at 100° C. for 30 min. The reaction was cooledto room temperature, added a small portion of Si-THIOL to get rid ofPalladium. The mixture was filtered and purified via C₁₈ reverse phaseHPLC to give the final product. LC-MS Retention Time: t₁ (Method1)=7.100 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.33 (s, 1H), 10.52 (s,1H), 8.50 (d, J=8.2 Hz, 1H), 7.93 (dd, J=7.8, 2.0 Hz, 1H), 7.71-7.80 (m,2H), 7.59-7.64 (m, 1H), 7.53-7.59 (m, 1H), 7.51 (ddd, J=8.5, 7.1, 2.0Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.18 (d, J=8.6Hz, 1H), 7.00-7.10 (m, 2H), 6.39 (dd, J=11.7, 2.3 Hz, 1H), 5.60-5.92 (m,1H), 4.27 (q, J=6.9 Hz, 2H), 1.86 (dd, J=7.4, 2.0 Hz, 3H), 1.30 (t,J=6.8 Hz, 3H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₅N₂O₃, 401.1860;found 401.1862.

Example 186

This example illustrates a synthesis ofN-(3-Cyanophenyl)-2-(2-ethoxybenzamido)benzamide (XJB11-080,NCGC00250133-01). The title compound was prepared according to generalprotocol A. LC-MS Retention Time: t₁ (Method 1)=6.342 min; ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.28 (s, 1H), 10.83 (s, 1H), 8.49 (d, J=7.8 Hz,1H), 8.22 (t, J=1.6 Hz, 1H), 7.95-8.04 (m, 1H), 7.93 (dd, J=7.8, 2.0 Hz,1H), 7.78 (dd, J=7.8, 2.0 Hz, 1H), 7.54-7.63 (m, 3H), 7.51 (ddd, J=8.5,7.1, 2.0 Hz, 1H), 7.23-7.33 (m, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.00-7.13(m, 1H), 4.29 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.0 Hz, 3H); HRMS (ESI) m/z(M+H)⁺ calcd. for C₂₃H₂₀N₃O₃, 386.1499; found 386.1515.

Example 187

This example illustrates a synthesis of Methyl2-amino-3-(2-ethoxybenzamido)benzoate (XJB11-082). A solution of2,3-diaminobenzoate (100 mg, 0.602 mmol) in dichloromethane (5.00 mL)and TEA (0.252 mL, 1.81 mmol) was treated at 0° C. with 2-ethoxybenzoylchloride (111 mg, 0.602 mmol). The reaction mixture was stirred at 0° C.for 1 h. The reaction mixture was concentrated in vacuo and the crudematerial was used directly in the next reaction.

Example 188

This example illustrates a synthesis of Methyl2-(2-ethoxyphenyl)-1H-benzo[d]imidazole-4-carboxylate (XJB11-083). Asolution of methyl crude 2-amino-3-(2-ethoxybenzamido)benzoate (189 mg,0.602 mmol) in glacial acetic acid (3.00 mL) was heated at 70° C. for 24h. The reaction mixture was concentrated in vacuo; and the crude residuewas purified via silica gel chromatography using a gradient of 0-20% ofMeOH in dichloromethane to give 165 mg (92%) of the title compound as awhite solid. LC-MS Retention Time: t₂ (Method 2)=3.088 min; m/z (M+H)⁺297.1.

Example 189

This example illustrates a synthesis of2-(2-Ethoxyphenyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide(XJB11-086, NCGC00250115-01). The title compound was prepared accordingto general protocol A. LC-MS Retention Time: t₁ (Method 1)=6.265 min;HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₁₉F₃N₃O₄S, 490.1043; found490.1049.

Example 190

This example illustrates a synthesis of tert-Butyl(2-formylphenyl)carbamate (XJB11-088). A solution of tert-butyl2-(hydroxymethyl)phenylcarbamate (0.370 g, 1.66 mmol) and Dess-MartinPeriodinane (0.914 g, 2.15 mmol) in dichloromethane (15.0 mL) wasstirred at 0° C. for 1 h. The reaction mixture was concentrated and thecrude residue was purified via silica gel chromatography using 10% ofEtOAc in hexanes to give 300 mg (82%) of the title compound as acolorless oil.

Example 191

This example illustrates a synthesis of tert-Butyl(2-(((3-((trifluoromethyl)sulfonyl)phenyl)amino)methyl)phenyl)carbamate(XJB11-090). A mixture of tert-butyl 2-formylphenylcarbamate (80.0 mg,0.362 mmol) and 3-(trifluoromethylsulfonyl)aniline (122 mg, 0.542 mmol)in MeOH (2.00 ml) was treated with Ti(O^(i)Pr)₄ (0.212 mL, 0.723 mmol).The reaction was stirred at room temperature for 6 h, then treated withNaBH₄ (20.5 mg, 0.542 mmol) and stirred overnight at room temperature.The reaction mixture was poured into 2N NH₄OH aqueous solution, theresulting inorganic precipitate was filtered off, and the filtrate wasextracted with EtOAc. The organic layer was separated, dried andconcentrated to give the final product as a colorless oil which was useddirectly in the next reaction. LC-MS Retention Time: t₂ (Method 2)=3.869min; m/z (M+H)⁺ 431.1.

Example 192

This example illustrates a synthesis ofN-(2-Aminobenzyl)-3-((trifluoromethyl)sulfonyl)aniline (XJB11-091). Asolution of tert-butyl2-((3-(trifluoromethylsulfonyl)phenylamino)methyl)phenylcarbamate (0.156g, 0.362 mmol) in dichloromethane (2.00 mL) was treated at 0° C. withTFA (2.00 mL, 26.0 mmol). The reaction mixture was stirred at roomtemperature for 1 h. The mixture was concentrated to give the finalproduct which was used directly in the next reaction.

Example 193

This example illustrates a synthesis of2-Ethoxy-N-(2-(((3-((trifluoromethyl)sulfonyl)phenyl)amino)methyl)phenyl)benzamide(XJB11-097, NCGC00250112-01). A solution ofN-(2-aminobenzyl)-3-(trifluoromethylsulfonyl)aniline (0.060 g, 0.181mmol) in dichloromethane (2.00 mL) and TEA (0.075 mL, 0.535 mmol) wastreated at 0° C. with 2-ethoxybenzoyl chloride (0.033 g, 0.181 mmol).The reaction mixture was stirred overnight at room temperature for 2 h.The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filteredand purified via C₁₈ reverse phase HPLC to give the final product. LC-MSRetention Time: t₁ (Method 1)=6.813 min; HRMS (ESI) m/z (M+H)⁺ calcd.for C₂₃H₂₂F₃N₂O₄S, 479.1247; found 479.1249.

Example 194

This example illustrates a synthesis of7-Amino-2-(3-(trifluoromethyl)phenyl)isoindolin-1-one (XJB11-098). Amixture of 7-aminoisoindolin-1-one (80.0 mg, 0.540 mmol),1-iodo-3-(trifluoromethyl)benzene (176 mg, 0.648 mmol),(1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.017 mL, 0.108 mmol),CuI (5.1 mg, 0.027 mmol) and K₂CO₃ (149 mg, 1.08 mmol) in toluene (3.00mL) was stirred overnight at 110° C. The reaction mixture wasconcentrated and the crude residue was purified via silica gelchromatography using a gradient of 0-100% of EtOAc in hexanes to give39.0 mg (25%) of the title compound as a white solid. LC-MS RetentionTime: t₂ (Method 2)=3.736 min; m/z (M+H)⁺ 293.1.

Example 195

This example illustrates a synthesis of2-Ethoxy-N-(3-oxo-2-(3-(trifluoromethyl)phenyl)isoindolin-4-yl)benzamide(XJB12-002, NCGC00250113-01). A solution of7-amino-2-(3-(trifluoromethyl)phenyl)isoindolin-1-one (18.0 mg, 0.062mmol) in dichloromethane (1.00 mL) and TEA (0.026 mL, 0.185 mmol) wastreated at 0° C. with 2-ethoxybenzoyl chloride (17.1 mg, 0.092 mmol).The reaction mixture was stirred overnight at room temperature for 2 h.The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filteredand purified via C₁₈ reverse phase HPLC to give the final product. LC-MSRetention Time: t₁ (Method 1)=7.538 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.04 (s, 1H), 8.98 (d, J=8.2 Hz, 1H), 8.76 (s, 1H), 8.35 (dd, J=8.2,2.7 Hz, 1H), 8.27 (dd, J=7.8, 2.0 Hz, 1H), 7.93-8.05 (m, 2H), 7.79-7.92(m, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.35-7.50 (m,1H), 5.41 (s, 2H), 4.72 (q, J=6.8 Hz, 2H), 1.68-1.82 (t, J=7.2 Hz, 3H);¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −61.34 (s, 3 F); HRMS (ESI) m/z (M+H)⁺calcd. for C₂₄H₂₀F₃N₂O₃, 441.1421; found 441.1429.

Example 196

This example illustrates a synthesis ofN-(3-(1H-tetrazol-5-yl)phenyl)-2-(2-ethoxybenzamido)benzamide(XJB12-006, NCGC00250114-01). A solution ofN-(3-cyanophenyl)-2-(2-ethoxybenzamido)benzamide (0.066 g, 0.171 mmol)in water (1.00 mL) was treated at room temperature with ZnBr₂ (0.058 g,0.257 mmol) and NaN₃ (0.033 g, 0.513 mmol). The pH value of the solutionwas adjusted to ˜7 by several drops of 1 N NaOH aqueous solution. Thereaction mixture was heated at 120° C. for 60 hours. Another aliquot ofreagents was added and the mixture was heated at 120° C. for anadditional 24 h. The reaction mixture filtered and purified via C₁₈reverse phase HPLC to give two products NCGC00250114-01 andNCGC00250134-01. LC-MS Retention Time: t₁ (Method 1)=5.547 min; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.36 (s, 1H), 10.77 (s, 1H), 8.61 (t, J=2.0Hz, 1H), 8.52 (d, J=8.2 Hz, 1H), 7.93 (dd, J=7.8, 2.0 Hz, 1H), 7.85-7.91(m, 1H), 7.81 (dd, J=7.8, 1.6 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.53-7.63(m, 2H), 7.50 (ddd, J=8.6, 7.0, 2.0 Hz, 1H), 7.23-7.31 (m, 1H), 7.18 (d,J=8.2 Hz, 1H), 7.01-7.10 (m, 1H), 4.30 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0Hz, 3H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₁N₆O₃, 429.1670; found429.1673.

Example 197

This example illustrates a synthesis ofN-(3-Carbamimidoylphenyl)-2-(2-ethoxybenzamido)benzamide (XJB12-008,NCGC00250116-01). A suspension of ammonium chloride (267 mg, 5.00 mmol)in benzene (5.00 mL) at 5° C., was slowly added a trimethylaluminum (2.0M in toluene, 2.50 mL, 5.00 mmol). After the addition was completed, thereaction mixture was allowed to warm to room temperature and was stirredfor 1-2 hours until gas evolution has ceased. The solution was ready touse. 0.394 mL of above in situ solution was added to another solution ofN-(3-cyanophenyl)-2-(2-ethoxybenzamido)benzamide (50.0 mg, 0.130 mmol)in toluene (1.00 mL) at room temperature. The reaction mixture washeated under argon at 80° C. for 4 h. The reaction mixture was filteredthrough a pad of celite and concentrated as a yellow oil. The crudematerial was re-dissolved in 2.00 mL of DMSO, filtered and purified viaC₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time:t₁ (Method 1)=4.349 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.36 (s, 1H),10.78 (s, 1H), 8.58-8.64 (m, 1H), 8.52 (d, J=8.2 Hz, 1H), 7.93 (dd,J=7.6, 2.2 Hz, 1H), 7.87 (dd, J=8.2, 2.7 Hz, 1H), 7.81 (dd, J=7.8, 2.0Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.53-7.62 (m, 2H), 7.50 (ddd, J=8.6,7.0, 2.0 Hz, 1H), 7.24-7.32 (m, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.06 (t,J=7.6 Hz, 1H), 4.30 (q, J=7.0 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H) (3 N—Hprotons didn't show up); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₃N₄O₃,403.1765; found 403.1766.

Example 198

This example illustrates a synthesis of3-(4-(1H-Tetrazol-5-yl)phenyl)-2-(2-ethoxyphenyl)quinazolin-4(3H)-one(XJB12-010, NCGC00250134-01). The title compound was prepared as aby-product of synthesizingN-(3-(1H-tetrazol-5-yl)phenyl)-2-(2-ethoxybenzamido)benzamide(XJB12-006, NCGC00250114-01). LC-MS Retention Time: t₁ (Method 1)=5.100min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₁₉N₆O₂, 411.1564; found411.1569.

Example 199

This example demonstrates activation of the RXFP1 receptor resulting instimulation of cAMP production by several embodiments of the disclosurein the RXFP1 cAMP assay in HEK293-RXFP1 cells

The RXFP1 receptor couples to the Gs protein, and activation of thereceptor results in stimulation of cAMP production. To screen foragonists of the receptor, RXFP1 was stably expressed in human embryonickidney cells (HEK293-RXFP1), which have previously been show toconstitute a functional cell-based model for RXFP1-cAMP signalingpathway.^(16,17) Cyclic AMP levels were detected using the HTRF cAMPassay kit.¹⁸ This assay uses a europium cryptate labeled anti-cAMPantibody (K-α-cAMP) and d2 dye labeled cAMP (cAMP-d2) as a tracer in atime-resolved fluorescence energy transfer (TR-FRET) detection system.The TR-FRET between the K-α-cAMP and cAMP-d2 is disrupted by cAMP in thecell lysates, thus allowing TR-FRET detection in a homogenous formatthat is suitable for HTS. The assay was carried out in the presence of aphosphodiesterase 4 (PDE4) inhibitor, Ro 20-1724, to amplify cAMPsignal. The primary screen was carried out in 1536-well format, however,because of a more robust signal to background ratio, all subsequentfollow-up experiments were carried out in 384-well format.

For the primary screen, HEK293-RXFP1 cells were seeded at 2,000cells/well in 3 μL/well media with a MultiDrop Combi dispenser (ThermoScientific, Logan, Utah), and allowed to attach overnight at 37° C., 5%CO₂. Next, 1 μL/well of 400 μM Ro 20-1724 in PBS was added, followed byaddition of 23 nL/well of compound solution in DMSO with a pintooltransfer (Kalypsys, San Diego, Calif.). The cells were allowed to bestimulated with the compounds for 30 minutes at 37° C., 5% CO₂, afterwhich, 1 μL/well of each HTRF detection reagent was dispensed with aBioRAPTR FRD dispenser. The detection reagents were diluted beforeaddition as follows: K-α-cAMP antibody at 1:20 and cAMP-d2 at 1:18 inHTRF lysis buffer (supplied by the assay kit). The plates were incubatedfor 30 minute at room temperature, and then the signal was read on aViewLux plate reader (PerkinElmer, Waltham, Mass.).

The assay was run according to the following protocol:

Sequence Parameter Value Description 1 Cells 3 μL 2,000 cells/well 2Time 16-24 h Incubate at 37° C. and 5% CO₂ 3 Reagent 1 μL 400 μM Ro20-1724 in PBS 4 Reagent 23 nL Compound library, forskolin as control 5Time 30 min Incubate at 37° C. and 5% CO₂ 6 Reagent 1 μL cAMP-d2 diluted1:18 in lysis buffer 7 Reagent 1 μL K-α-cAMP diluted 1:20 in lysisbuffer 8 Time 30 min Room temperature incubation 9 Detector TR-FRETViewLux plate reader

The results are set forth in Tables 1-7, wherein AC₅₀ (μM) indicates thepotency of the compound in micromolar, or more specifically theconcentration at which the compound activates the functional activity ofthe receptor by its half-maximal amount. Max Response indicates what themaximal amount of functional activity induced by the compound is, as apercentage of the maximal receptor activation induced by highconcentrations of forskolin.

TABLE 1

RXFP1 Max # NHR₂ AC₅₀ (μM) Response 1

1.88 92% 2

94.0 57% 3

inactive N/A 4

37.4 65% 5

187 32% 6

94.0 46% 7

2.65 70% 8

inactive N/A 9

37.4 74% 10

inactive N/A 11

inactive N/A 12

13.3 81% 13

37.4 74% 14

inactive N/A 15

2.65 91% 16

118 50% 17

inactive N/A 18

5.93 93% 19

74.7 56% 20

5.29 66% 21

6.66 85% 22

inactive N/A 23

3.34 89% 24

2.97 84% 25

inactive N/A 26

5.29 84% 27

118 34% 28

1.88 90% 29

1.06 87% 30

inactive N/A 31

471 31% 32

2.65 74% 33

inactive N/A 34

inacitve N/A 35

9.40 46% 36

74.7 58% 37

inactive N/A 38

inactive N/A 39

inactive N/A 40

inactive N/A 41

inactive N/A 42

149 31% 43

118 40% 44

9.40 45%

TABLE 2

RXFP1 Max # COR₃ AC₅₀ (μM) Response 45

1.88 92% 46

47.1 78% 47

74.7 51% 48

5.29 59% 49

5.29 94% 50

5.29 79% 51

8.38 79% 52

2.97 75% 53

2.36 88% 54

2.36 92% 55

4.71 87% 56

2.11 75% 57

1.32 64% 58

8.38 86% 59

5.93 81% 60

14.9 85% 61

6.66 81% 62

11.8 90% 63

14.9 93% 64

2.36 81% 65

1.88 88% 66

5.93 95% 67

7.47 51%

TABLE 3

RXFP1 Max # COR₃ AC₅₀ (μM) Response 68

1.88 92% 69

1.32 64% 70

7.47 70% 71

2.97 95% 72

5.93 93% 73

4.20 94% 74

0.334 99% 75

1.88 94% 76

9.40 71% 77

4.20 90% 78

3.74 92% 79

4.71 85% 80

3.74 92% 81

1.88 96% 82

2.65 95% 83

7.47 78% 84

1.67 97% 85

4.20 93% 86

7.47 80% 87

1.06 84% 88

188 30% 89

1.49 96% 90

2.10 96% 91

1.67 96% 92

5.29 89% 93

9.40 77% 94

5.93 71%

TABLE 4

RXFP1 Max AC₅₀ Re- # COR₃ (μM) sponse 95

1.88 92% 96

1.32 64% 97

0.334 99% 98

1.18 96% 99

0.265 94% 100

0.471 99% 101

0.747 97% 102

7.47 42% 103

0.747 98% 104

3.74 92% 105

59.3 66% 106

4.71 98% 107

2.65 99% 108

1.33 94% 109

inactive N/A

TABLE 5

RXFP1 Max # R₁ AC₅₀ (μM) Response 110

1.88 92% 111

1.32 64% 112

0.334 99% 113

5.93 77% 114

47.1 69% 115

59.3 57% 116

4.20 84% 117

4.71 77% 118

4.20 93% 119

47.1 71% 120

9.40 83% 121

59.3 63% 122

inactive N/A 123

inactive N/A 124

inactive N/A 125

inactive N/A 126

inactive N/A 127

inactive N/A 128

inactive N/A 129

inactive N/A 130

inactive N/A 131

inactive N/A

TABLE 6

RXFP1 Max # R_(A) Linker 1 R_(B) AC₅₀ (μM) Response 132                  133             134                    

CF₃                   CF₃             CF₃  1.88                  inactive             inactive 92%                   N/A             N/A135           136           137           138             139                       

CF₃           CF₃           CF₃         CF₃             CF₃   0.334          inactive           inactive         inactive              29.7 99%          N/A           N/A         N/A             77% 140

inactive N/A 141

149 31% 142

188 34% 143

149 36% 144               145               146             147                               

SO₂CF₃               SO₂CF₃               SO₂CF₃             SO₂CF₃ 0.118                2.65                4.71              2.36 99%              77%               90%             95% 148           149          150             151           152

SO₂CF₃           SO₂CF₃           SO₂CF₃             SO₂CF₃          SO₂CF₃ inactive            1.67            2.97              0.747           4.71 N/A           98%           99%             97%           73%153

SO₂CF₃ inactive N/A 154

SO₂CF₃ inactive N/A

TABLE 7

RXFP1 Max AC₅₀ Re- # R_(C) R₂ (μM) sponse 155 OMe

0.334 99% 156 OMe

1.33 94% 157 OMe

6.66 95% 158 OMe

0.297 99% 159 OMe

0.188 99% 160 OMe

inactive N/A 161 OMe

5.29 77% 162 OEt

29.7 74% 163 OEt

149 37% 164 OEt

74.7 64% 165 OEt

11.8 72% 166 OEt

0.747 96% 167 OEt

1.06 93% 168 OEt

2.11 84% 169 OEt

1.49 91% 170 OEt

0.666 96% 171 OEt

inactive N/A 172 OEt

inactive N/A 173 OEt

0.666 98% 174 OEt

0.188 99% 175 I

4.20 85% 176 SEt

0.529 95% 177 OCH₂CF₃

0.067 97% 178 OCH(CH₃)₂

0.094 98% 179 OCH₂CH₂CH₃

0.052 98% 180 OCH₂CH₂CH₂CH₃

0.047 98%

Example 200

This example illustrates the activation of VEGF expression in THP1 cellsby several embodiments of the disclosure.

THP1 cells (human acute monocytic leukemia cell line) were used toanalyze the stimulation of VEGF gene expression after treatment withrelaxin or compounds. The VEGF stimulation in these cultured endometrialcells is a well-established property of relaxin.¹⁹ This effect is mostprobably responsible for the observed angiogenic and neovascularizationproperties of relaxin in various settings.²⁰ 400,000 THP1 cells (0.4 mLat 1×10⁶ cells/mL) in test media (RPMI-1640 without phenol red, 0.5%FBS, Ix Pen/Strep, 0.05 mM of 2-mercaptoethanol) were seeded in eachwell on a 24-well plate. After 24 hours incubation at 37° C., 5% CO₂,relaxin or compounds were added for 2 hours. The cells were harvestedand RNA was extracted by the Trizol (Invitrogen, Carlsbad, Calif.)method according to manufacturers' instructions. cDNA was synthesized byusing Verso cDNA kit (Thermo Scientific, Waltham, Mass.) according tomanufacturer's protocol. Quantitative real time RT-PCR for VEGF andGAPDH gene expression was done using a Roche LightCycler 480 (RocheDiagnostics, Indianapolis, Ind.) with the appropriate set of primers andprobes spanning different exons. The relative fold change in VEGF mRNAlevel was calculated by the comparative C_(t) (2-ΔΔ^(Ct)) method usingGAPDH expression for normalization of RNA.

The results are set forth in Table 8 as relative VEGF gene expressionrelative to control.

TABLE 8 Compound Relative VEGF gene expression (control = 1.0) Relaxin2.5 158 1.2 177 1.3 179 1.5 180 1.6 99 1.9 174 2.3 178 2.8 159 1.4

As is apparent from the results set forth, all of the compounds with thepossible exception of compound 158 exhibited a significant upregulationof VEGF expression. Compound 178 exhibited a greater upregulation ofVEGF expression than did relaxin.

Example 201

It was previously shown that relaxin increases cell impedance in RXFP1transfected cells. Cell-substrate impedance was measured using a RocheDP RTCA xCELLigence Analyzer (Roche Diagnostics, Indianapolis, Ind.) onE-Plates. Real Time Cell Analyzer (RTCA) allows for continuoustime-resolved measurement of cellular index without additional labeling.Cell number, cellular adherence to the plate, and intracellularinteractions all contribute to the total cellular impedance. The effectof the compound treatment is only measured within the first hour,changes in cellular density are unlikely to contribute to the overalleffect, and therefore cellular impedance is most likely caused byintercellular interactions, or signaling.

Cell Index (CI) was calculated by subtracting impedance at the beginningof experiment Z₀ from impedance at each individual time point Z_(t),divided by 15Ω [CI_(t)=(Z₀−Z_(t))/15Ω]. Delta Cellular Indices werecalculated as the change of impedance at a given time t, from the timeof compound addition (CI_(compound)) ΔCI_(t)=CI_(t)−CI_(compound).Impedance at each time point was then normalized to the average ofquadruplicate CI of cells treated with vehicle (V1, V2, V3, and V4), tocalculate normalized delta Cell IndexNΔCI=(CI_(t)−CI_(compound))/Average[ΔCI_(V1), ΔCI_(V2), ΔCI_(V3),ΔCI_(V4)]. Maximal relaxin activity was assigned a value of 100% and allother values adjusted proportionally.

The cell line stably transfected with RXFP1 receptor HEK293-RXFP1 wasused for cell impedance assay to confirm relaxin-like properties of thecompounds. To equilibrate the plates, 100 μL of test media (DMEM, 1%FBS, lx Pen/Strep) was added to each well of E-Plate (Roche Diagnostics,Indianapolis, Ind.) and the plate was incubated at room temperature for30 minutes at which point baseline impedance was measures. Then 20,000HEK293-RXFP1 cell or HEK293 cells (parental control cell line) wereadded per well in a volume of 100 μL test media and allowed to sedimentat room temperature for 30 minutes. The plate was placed intoxCELLigence RTCA DP Instrument in the CO₂ incubator overnight to allowthe cells to attach. Relaxin (10 ng/mL), vehicle, or compounds atdifferent concentrations (250, 500, and 750 nM) were added to the wellsand the cellular impedance was measured every 10-30 seconds for 1 hour.The protocol was as follows:

Sequence Parameter Value Description 1 Cells 200 μL 20,000 cells/well 2Time Overnight Incubate at 37° C. and 5% CO₂ 3 Reagent 50 μL Compoundsin DMEM and 1% FBS, relaxin as positive control, and vehicle as abaseline 4 Time 1 h Incubate at 37° C. and 5% CO₂ 5 Detector impedanceRTCA DP Instrument 6 Cells 200 μL 20,000 cells/well

The results are set forth in FIG. 8.

Example 202

This Example illustrates the cyclic AMP assay in THP-1 cells. THP-1cells were propagated in RPMI-1640 supplemented with 20% FBS, 0.05 mMβ-mercaptoethanol, 100 U/mL penicillin and 100 μg/mL streptomycin at 37°C. in 5% CO₂. Before assaying for cAMP response, cells were serumstarved in RPMI-1640 supplemented with 0.05 mM (3-mercaptoethanol, 100U/mL penicillin and 100 μg/mL streptomycin at 37° C. in 5% CO₂ for 16hrs. For 384-well format assays, cells were seeded as 30,000 cells/wellin 30 μL/well media with a MultiDrop Combi dispenser (Thermo Scientific,Waltham, Mass.). Subsequently, 2 μL/well of 1.6 mM Ro 20-1724 and 160 uMforskolin in PBS+ (DPBS, 1 mM CaCl₂, 0.5 mM MgCl₂, 0.05% BSA, 0.005%Tween 20) was dispensed using a BioRAPTR FRD dispenser (Beckman Coulter,Brea, Calif.). Immediately after, 0.25 μL/well of compound solutions inDMSO was dispensed with CyBi-well dispenser (CyBio, Jena, Germany). Thecells were allowed to be stimulated with compounds for 30 min at 37° C.in 5% CO₂, after which, 8 μL/well of each HTRF cAMP HiRange kit (CisBio,Bedford, Mass.) detection reagent was dispensed with a BioRAPTR FRDdispenser. The detection reagents were diluted as such: K-α-cAMPantibody at 1:20 and cAMP-d2 at 1:18 in HTRF lysis buffer (supplied bythe assay kit). The plates were incubated for 30 min at room temperaturebefore the signal was read on an Envision plate reader (PerkinElmer,Waltham, Mass.). The EC₅₀ values for selected embodiments are set forthin Table 9.

TABLE 9 Compound EC₅₀ 99 0.4711 158 0.5231 159 0.3585 174 0.3622 1770.1073 178 0.1999 179 0.1051 180 0.1237

Example 203

This example demonstrates the RXFP2 cAMP assay in HEK293-RXFP2 cells.HEK293 cells stably transfected with RXFP2, the cognate receptor foranother relaxin family peptide, insulin-like 3, (HEK293-RXFP2) was usedto test compound specificity towards the RXFP1 receptor. For this assay,cells were seeded at 8,000 cells/well in 30 L/well of media with aMultiDrop Combi dispenser (Thermo Scientific), and allowed to attachovernight at 37° C., 5% CO₂. Next, 2 L/well of 1.6 mM Ro 20-1724solution in PBS+(DPBS, 1 mM CaCl₂, 0.5 mM MgCl₂, 0.05% BSA, 0.005% Tween20) were dispensed using a BioRAPTR FRD dispenser (Beckman Coulter,Brea, Calif.), followed addition of 0.25 μL/well of compound solution inDMSO with CyBi-well dispenser (CyBio, Jena, Germany). The cells wereallowed to be stimulated with the compounds for 30 minutes at 37° C., 5%CO₂, after which, 8 μL/well of each HTRF detection reagent (dilutedaccording to assay kit directions in HTRF lysis buffer) was dispensedwith a BioRAPTR FRD dispenser. The plates were incubated for 30 minuteat 37° C., and then the signal was read on a ViewLux plate reader(PerkinElmer, Waltham, Mass.). The protocol was as follows:

Sequence Parameter Value Description 1 Cells 30 μL 8,000 cells/well 2Time 16-24 h Incubate at 37° C. and 5% CO₂ 3 Reagent 2 μL 1600 μM Ro20-1724 in PBS 4 Reagent 2.5 μL Compounds in DMSO, forskolin as control5 Time 30 min Incubate at 37° C. and 5% CO₂ 6 Reagent 8 μL cAMP-d2diluted 1:18 in lysis buffer 7 Reagent 8 μL K-α-cAMP diluted 1:20 inlysis buffer 8 Time 30 min Room temperature incubation

Example 204

This example demonstrates the V1b cAMP assay in HEK293-V1b cells. HEK293stably transfected with a nonrelated G protein coupled receptor,vasopressin receptor 1b (HEK293-V1b), were used as an additional counterscreen to eliminate compounds that increase cAMP HTRF signal throughnon-RXFP1 dependent mechanisms. For this assay, cells were seeded at8,000 cells/well in 30 L/well media with a MultiDrop Combi dispenser(Thermo Scientific, Logan, Utah), and allowed to attach overnight at 37°C., 5% CO₂. Next, 2 μL/well of 1.6 mM Ro 20-1724 solution in PBS+(DPBS,1 mM CaCl₂, 0.5 mM MgCl₂, 0.05% BSA, 0.005% Tween 20) was dispensedusing a BioRAPTR FRD dispenser (Beckman Coulter, Brea, Calif.), followedby additional of 0.25 μL/well of compound solution in DMSO withCyBi-well dispenser (CyBio, Jena, Germany). The cells were allowed to bestimulated with the compounds for 30 minutes at 37° C., 5% CO₂, afterwhich, 8 μL/well of each HTRF detection reagent (diluted according toassay kit directions in HTRF lysis buffer) was dispensed with a BioRAPTRFRD dispenser. The plates were incubated for 30 minute at roomtemperature, and then the signal was read on a ViewLux plate reader(PerkinElmer, Waltham, Mass.). The protocol was as follows:

Sequence Parameter Value Description 1 Cells 30 μL 8,000 cells/well 2Time 16-24 h Incubate at 37° C. and 5% CO₂ 3 Reagent 2 μL 1,600 μM Ro20-1724 in PBS 4 Reagent 2.5 μL Compounds in DMSO, forskolin as control5 Time 30 min Incubate at 37° C. and 5% CO₂ 6 Reagent 8 μL cAMP-d2diluted 1:18 in lysis buffer 7 Reagent 8 μL K-α-cAMP diluted 1:20 inlysis buffer 8 Time 30 min Room temperature incubation 9 DetectorTR-FRET EnVision plate reader

Example 205

This example demonstrates the ATP Cytotoxicity assay in HEK293-RXFP1cells. This follow-up assay was conducted to measure the effect ofcompounds on cell viability by measuring ATP levels (ATPLite™). ATPLite™is an Adenosine TriPhosphate (ATP) monitoring system based on firefly(Photinus pyralis) luciferase. The level of ATP in a metabolicallyactive cell is a general marker for its viability. ATP levels are oftenreduced during necrosis or apoptosis. In this assay, the luciferaseenzyme catalyzes the conversion of the added substrate D-luciferin tooxyluciferin and light with ATP. Thus, the emitted light is proportionalto the ATP concentration. To evaluate the cytotoxic properties of thecompounds, HEK293-RXFP1 cells were incubated with compounds for 72 hoursin growth media (DMEM 10% FBS, lx Pen/Strep, 0.5 mg/mL of G418) in384-well format. After compound incubation, the levels of ATP in eachwell were measured with the addition of the ATPLite assay reagent. Theprotocol was as follows:

Sequence Parameter Value Description 1 Cells 30 μL 1,000 cells/well 2Time 16-24 h Incubate at 37° C. and 5% CO₂ 3 Reagent 2.5 μL Compounds inDMSO 4 Time 72 h Incubate at 37° C. and 5% CO₂ 5 Reagent 20 μL ATPLite(PerkinElmer) 6 Time 15 min Room temperature incubation 7 DetectorLuminescence ViewLux plate reader

Example 206

This example illustrates the activity of several embodiments of thedisclosure in the RXFP1 assay (Example 199), the RXFP2 assay (Example203), the V1b assay (Example 204), and the ATP toxicity (Example 202),as well as the PBS solubility and the mouse liver microsome (MLM)stability. The results are set forth in Table 10.

TABLE 10 RXFP1 AC₅₀ RXFP2 AC₅₀ V1b AC₅₀ ATP Tox. EC₅₀ PBS Solubility MLMStability Entry Internal ID (μM, Max. Resp.) (μM, Max. Resp.) (μM, Max.Resp.) (μM, Max. Resp.) (μM) (t₁/₂ in min.) 37 99 0.297 (95%) 9.40 (47%)inactive^(a) inactive^(a) 1.7 N/A 61 158 0.297 (99%) 3.34 (54%)inactive^(a) 3.74 (−31%) 2.9 N/A 62 159 0.188 (99%) inactive^(a)inactive^(a) 29.7 (−76%) 6.3 N/A 63 174 0.188 (99%) 7.47 (38%)inactive^(a) 18.8 (−73%) <1.1 1732 65 177 0.067 (97%) inactive^(a)inactive^(a) 29.7 (−78%) 3.3 100 66 178 0.094 (98%) inactive^(a)inactive^(a)  9.4 (−85%) 7.0 122 ML290 67 179 0.052 (98%) inactive^(a)inactive^(a)  9.4 (−83%) 17.0 133 68 180 0.047 (98%) inactive^(a)inactive^(a) 59.3 (−53%) 5.3 178 ^(a)Maximum response less than 30%.

Example 207

Referring to FIG. 9, 1-3ECL are extracellular loops of transmembranedomains of RXFP1. This example demonstrates the ability of compound toactivate human but not mouse relaxin receptor transfected in HEK293cells as measured by cAMP accumulation. The compound was inactiveagainst related to RXFP1 mouse relaxin family receptor 2, RXFP2. Thechimeric mouse/human RXFP1 receptors were activated by compounds only ifthey contained the region encoded by human exon 17 plus two humanizedcodons from exon 18. The 3′-end of mouse and human exon 17 encodes the3^(rd) ECL. There are 4 amino acid differences between human and mouse3EXL. Two mouse site-specific mutants were tested, one where isoleucine646 and leucine 647 were substituted by two valines specific for humansequence (M10), and the other one where aspartic acid (position 659) andserine (660) were substituted by glycine and threonine (M11). Both didnot respond to the compound stimulation.

Example 208

Example 208 provides a method for synthesizing radiolabelled precusors.

Example 209

Example 209 provides a method for preparing tritium ³H labeled analogsof the Relaxin Receptor 1 modulators disclosed herein.

Example 210

Example 210 provides a method for preparing fluorine-18 (¹⁸F) labeledanalogs of the Relaxin Receptor 1 modulators disclosed herein.

Example 211

Synthesiso of tert-Butyl (2-((3-((trifluoromethyl)thio)phenyl)carbamoyl)phenyl)carbamate. A mixture of 2-((tert-butoxycarbonyl)amino)benzoicacid (2.50 g, 10.5 mmol) and 3-((trifluoromethyl)thio)aniline (2.44 g,12.6 mmol) in DMF (40.0 mL) was treated at room temperature with HATU(4.01 g, 10.5 mmol) and DIPEA (5.52 mL, 31.6 mmol). The reaction mixturewas stirred at room temperature overnight. The reaction mixture waspoured into ice water and extracted with EtOAc. The organic layer wasseparated, dried and concentrated as a brown oil. The crude material waspurified on silica gel with a gradient of 0-100% EtOAc in hexanes togive 3.20 g (yield 74%) of the title product as a white solid.

Example 212

Synthesis of tert-Butyl(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl) phenyl)carbamate. Asolution of tert-butyl (2-((3-((trifluoromethyl)thio)phenyl)carbamoyl)phenyl)carbamate (400 mg, 0.970 mmol) in mixed solvents of DCM (2.00mL), acetonitrile (2.00 mL) and water (4.00 mL) was treated at roomtemperature with sodium periodate (622 mg, 2.91 mmol). To thissuspension was added RuCl₃ (0.2 mg, 0.970 μmol). The reaction mixturewas stirred at room temperature overnight. The mixture was concentratedand re-disolved in water and DCM. The organic layer was separated, driedand concentrated to give a grey powder which was used directly in thenext reaction without further purification.

Example 213

Synthesis of 2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide. Asolution of crude tert-butyl(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl) carbamate(0.430 g, 0.970 mmol) in DCM (10.0 mL) was treated with TFA (5.00 mL) atroom temperature. The reaction mixture was stirred at room temperaturefor 30 minutes. The reaction mixture was concentrated and purified usingISCO on reverse phase column to give the desired product as a TFA salt.

Example 214

Synthesis of Ethyl 2-(but-3-en-1-yloxy)benzoate. A solution of ethyl2-hydroxybenzoate (0.442 mL, 3.01 mmol) and 4-bromobut-1-ene (1.22 g,9.03 mmol) in DMF (30.0 mL) was treated at room temperature with K₂CO₃(4.16 g, 30.1 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was filtered andconcentrated to give a yellow oil which was used directly in the nextreaction without further purification.

Example 215

Synthesis of 2-(But-3-en-1-yloxy)benzoic acid. A solution of ethyl2-(but-3-en-1-yloxy)benzoate (0.66 g, 3.01 mmol) in MeOH (15.0 mL) andwater (15.0 mL) was treated at room temperature with LiOH (0.72 g, 30.1mmol). The reaction mixture was stirred at room temperature overnight.The mixture was cooled to 0° C. and acidified with 1 N HCl until pH=1.The reaction mixture was extracted with DCM and the organic layer wasseparated, dried and concentrated to give a colorless oil. The crudeproduct was purified on silica gel with a gradient of 5-20% MeOH in DCMto give a colorless oil.

Example 216

Synthesis of2-(Allyloxy)-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide.A solution of 2-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl) benzamide,TFA salt (30.5 mg, 0.067 mmol) in DMF (2.00 mL) was treated at roomtemperature with 2-(allyloxy)benzoic acid (23.7 mg, 0.13 mmol), HATU(25.3 mg, 0.067 mmol) and DIPEA (0.058 mL, 0.33 mmol). The reactionmixture was stirred at room temperature for 2 days. The crude mixturewas purified on ISCO under reverse phase column to give the titleproduct as a grey solid.

Example 217

Synthesis of2-(But-3-en-1-yloxy)-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide. A solution of2-amino-N-(3-((trifluoromethyl)sulfonyl) phenyl)benzamide, TFA salt(10.0 mg, 0.022 mmol) in DMF (2.00 mL) was treated at room temperaturewith 2-(but-3-en-1-yloxy)benzoic acid (8.4 mg, 0.044 mmol), HATU (8.3mg, 0.022 mmol) and DIPEA (0.019 mL, 0.109 mmol). The reaction mixturewas stirred at room temperature for 2 days. The crude mixture waspurified on ISCO under reverse phase column to give the title product asa grey solid.

Example 218

Synthesis of 2-Butoxy-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide. A solution of2-(but-3-en-1-yloxy)-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (1.8 mg, 3.47 μmol) in amixed solvents of THF (0.60 mL) and water (0.20 mL) was treated at 0° C.with ruthenium (III) chloride (1.0 mg, 4.8 μmol). NaBH₄ (2.0 mg, 15.2μmol) was added slowly into the mixture. The reaction mixture wasstirred at room temperature for 15 minutes. The reaction mixture wasfiltered through a pad of celite and purified using reverse phase columnto give the desired product as a white powder. In the scaled upreaction, ruthenium (III) chloride can be catalytic and NaBH₄ will be 2equivalents.

Example 219

Identification of a human RXFP1 region responsible for activation bycompound 178 (FIG. 11). Human RXFP1 (hRXFP1) is fully activated (100%)after treatment with relaxin or compound 178. Mouse RXFP1 (mRXFP1) doesnot respond to compound 178 (marked as 0%) at 66 M. The RXFP1 containsthe extracellular, 7 transmembrane, and intracellular (ICD) domains.Using chimeric mouse-human receptors (m/hRXFP1) the region responsiblefor RXFP1 activation by compound 178 was mapped to the part containingextracellular loop 3 (ECL3) of 7 transmembrane domain. Alignment ofhRXFP1 and mRXFP1 shows two pairs of diverse amino acids within ECL3.The N-terminal IL to VV substitution in mRXFP1 (mRXFP1-M10) did notchange mouse receptor response, whereas C-terminal GT to DS substitutionin hRXFP1 (hRXFP1-M11) abolished its compound 178 dependent activation.The mRXFP1-M11 mutant was partially active and the mouse receptor withhumanized ECL3 (mRXFP1-M10/M11) was fully active after stimulation withcompound 178. The cAMP response to compound 178 (66 M) in cellstransfected with a specific construct was normalized to the response ofthe same cells to relaxin (15 nM). The results represent the average of3 independent experiments±s.e.m. repeated in quadruplicates. **P<0.01 vshRXFP1 by Student's t-test.

Example 220

Pharmacokinetics of compound 178 (NCGC00250135). The pharmacokinecticsof compound 178 (NCGC00250135) were determined in male C57/Bl6 miceafter a single intravenous (IV) administration of 3 mg/kg and oral (PO)administration of 30 mg/kg of compound 178. The data is present in TABLE11.

TABLE 11 IV PO (plas- (plas- IV PO Parameter Units ma) ma) (heart)(heart) AUClast hr*ng/mL 703 980 5190 2630 AUCINF_obs hr*ng/mL 745 10005690 2680 Cl_obs mL/min/kg 67.2 8.78 AUMClast hr*hr*ng/mL 3110 299028300 5780 MRTlast hr 4.4 3.1 5.5 2.2 Vss_obs L/kg 24.5 4.2 t½ hr 6.65.5 6.3 1.0 C0 ng/mL 499 2930 Tmax hr 0.5 1.5 Cmax ng/mL 306 1030Bioavailablity 14% (BA)

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the disclosureand does not pose a limitation on the scope of the disclosure unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe disclosure.

Embodiments of this disclosure are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those embodiments may become apparent to those of ordinary skill inthe art upon reading the foregoing description. The inventors expectskilled artisans to employ such variations as appropriate, and theinventors intend for the disclosure to be practiced otherwise than asspecifically described herein. Accordingly, this disclosure includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the disclosure unless otherwise indicatedherein or otherwise clearly contradicted by context.

The invention claimed is:
 1. A compound or pharmaceutically acceptablesalt thereof having the formula

where: R₁₀ and R₂₁ are each 0 to 3 substitutents independently chosenfrom hydroxyl, halogen, nitro, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy,mono- and di-(C₁-C₂alkyl)amino-, a C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;R₂₀ is NO₂, CN, C₂-C₁₀haloalkyl, C₁-C₁₀haloalkoxy, —SR₇, —SOR₇, or—SO₂R₇, where R₇ is C₁-C₁₀carbhydryl or C₁-C₁₀haloalkyl; and R₃ iscyclohexyl.
 2. A method for therapeutic intervention in a facet ofmammalian health that is mediated by a mammalian relaxin receptor 1, themethod comprising administering to a mammal in need thereof an effectiveamount of a compound or salt of claim 1, wherein the facet of mammalianhealth is heart failure.
 3. A compound or salt of the formula

wherein R₂ is selected from: